Vol. 27 (2022)

No. 01 DOI: 10.1186/s11658-021-00301-9 Volume 27 (2022) - 27:01
Authors Parisa Maleki Dana1, Fatemeh Sadoughi1, Zatollah Asemi1* and Bahman Yousef2,3*
Abstract Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered favan ring system in common. These natural compounds are known for their benefcial properties, such as free radical scavenging, decreasing oxidative stress, and modulating infammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in diferent aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also afect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).
Keywords Polyphenols, Curcumin, Resveratrol, Epigallocatechin gallate, Chemoresistance
Address and Contact Information 1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
2 Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

*Corresponding author: asemi_z@Kaums.ac.ir; bahmanusef@gmail.com
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No. 02 DOI: 10.1186/s11658-021-00302-8 Volume 27 (2022) - 27:02
Authors Yitong Chen1†, Tingben Huang2†, Zhou Yu2, Qiong Yu2, Ying Wang3, Ji’an Hu4*, Jiejun Shi1* and Guoli Yang2*
Abstract Sestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More signifcantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process.
Keywords Sestrins, Biological functions, Human diseases, Musculoskeletal system disease, Biomarker, Therapeutic target
Address and Contact Information 1 Department of Orthodontics, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China
2 Department of Implantology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China
3 Department of Oral Medicine, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang,China.
4 Department of Oral Pathology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China
*Corresponding author: hja@zju.edu.cn; sjiejun@zju.edu.cn; 7308037@zju.edu.cn
Yitong Chen and Tingben Huang contributed equally to this work
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No. 03 DOI: 10.1186/s11658-021-00299-0 Volume 27 (2022) - 27:03
Authors Anna M. Olszewska1, Adam K. Sieradzan2, Piotr Bednarczyk3, Adam Szewczyk4 and Michał A. Żmijewski1*
Abstract Background: Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic efects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane.
Methods: The efects of calcitriol on the potassium ion current were measured using the patch-clamp method modifed for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. Results: For the frst time, our results indicate that calcitriol directly afects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calciumindependent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite efect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identifed amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol infuences the expression of genes encoding potassium channels. Such a dual, genomic and nongenomic action explains the pleiotropic activity of calcitriol. Conclusions: Calcitriol can regulate the mitochondrial large-conductance calcium regulated potassium channel. Our data open a new chapter in the study of nongenomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.
Keywords Calcitriol, Large-conductance calcium-regulated potassium channel, Mitochondria, Patch-clamp
Address and Contact Information 1 Department of Histology, Medical University of Gdańsk, 1a Dębinki, 80-211 Gdańsk, Poland
2 Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
3 Department of Physics and Biophysics, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
4 Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
*Corresponding author: mzmijewski@gumed.edu.pl
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No. 04 DOI: 10.1186/s11658-021-00300-w Volume 27 (2022) - 27:04
Title Specifcity of H2O2 signaling in leaf senescence: is the ratio of H2O2 contents in diferent cellular compartments sensed in Arabidopsis plants?
Authors Ulrike Zentgraf*, Ana Gabriela Andrade‐Galan and Stefan Bieker
Abstract Leaf senescence is an integral part of plant development and is driven by endogenous cues such as leaf or plant age. Developmental senescence aims to maximize the usage of carbon, nitrogen and mineral resources for growth and/or for the sake of the next generation. This requires efcient reallocation of the resources out of the senescing tissue into developing parts of the plant such as new leaves, fruits and seeds. However, premature senescence can be induced by severe and long-lasting biotic or abiotic stress conditions. It serves as an exit strategy to guarantee ofspring in an unfavorable environment but is often combined with a trade-of in seed number and quality. In order to coordinate the very complex process of developmental senescence with environmental signals, highly organized networks and regulatory cues have to be in place. Reactive oxygen species, especially hydrogen peroxide (H2O2), are involved in senescence as well as in stress signaling. Here, we want to summarize the role of H2O2 as a signaling molecule in leaf senescence and shed more light on how specifcity in signaling might be achieved. Altered hydrogen peroxide contents in specifc compartments revealed a diferential impact of H2O2 produced in diferent compartments. Arabidopsis lines with lower H2O2 levels in chloroplasts and cytoplasm point to the possibility that not the actual contents but the ratio between the two diferent compartments is sensed by the plant cells.
Keywords Leaf senescence, Free oxygen radicals, ROS, Hydrogen peroxide, Stromules, Senescence regulation, Intracellular compartments
Address and Contact Information ZMBP (Centre of Plant Molecular Biology), University of Tübingen, Auf der Morgenstelle 32, 72076 Tübingen, Germany
*Corresponding author: ulrike.zentgraf@zmbp.uni-tuebingen.de
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No. 05 DOI: 10.1186/s11658-021-00304-6 Volume 27 (2022) - 27:05
Authors Xiaohui Pan1, Jin Guo3, Canjun Liu4, Zhanpeng Pan1, Zhicheng Yang2*, Xiang Yao1* and Jishan Yuan1*
Abstract Background: Osteosarcoma (OS) is a common primary bone malignancy. Long non-coding RNA HCG18 is known to play an important role in a variety of cancers. However, its role in OS and relevant molecular mechanisms are unclear.
Methods: Real-time quantitative PCR was performed to determine the expression of target genes. Function experiments showed the efects of HCG18 and miR-365a-3p on OS cell growth.
Results: HCG18 expression was increased in OS cell lines. Moreover, in vitro and in vivo experiments demonstrated that HCG18 knockdown inhibited OS cell proliferation. Mechanistically, HCG18 was defned as a competing endogenous RNA by sponging miR-365a-3p, thus elevating phosphoglycerate kinase 1 (PGK1) expression by directly targeting its 3ʹUTR to increase aerobic glycolysis.
Conclusion: HCG18 promoted OS cell proliferation via enhancing aerobic glycolysis by regulating the miR-365a-3p/PGK1 axis. Therefore, HCG18 may be a potential target for OS treatment.
Keywords HCG18, miR-365a-3p, PGK1, Osteosarcoma, Aerobic glycolysis
Address and Contact Information 1 Department of Orthopedics, The Afliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu, China
2 Department of Orthopedics, Changzhou No. 2 People’s Hospital, The Afliated Hospital of Nanjing Medical University, Changzhou, China
3 Department of Orthopedics, Zhenjiang First People’s Hospital Branch, Zhenjiang, People’s Republic of China.
4 Department of Respiratory Therapy, The Afliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu, China.
*Corresponding author: 727633793yzc@sina.com; yaoxiang6266@163.com; yuanjs2022@163.com
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No. 06 DOI: 10.1186/s11658-022-00308-w Volume 27 (2022) - 27:06
Authors Mohammad Raf Khezri1*, Reza Varzandeh1 and Morteza Ghasemnejad‐Berenji1,2*
Abstract Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarifed. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.
Keywords SARS-CoV-2, Coagulation, COVID-19, PI3K/AKT
Address and Contact Information 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Sero Road, 5715799313 Urmia, Iran
2 Research Center for Experimental and Applied Pharmaceutical Sciences, Urmia University of Medical Sciences, Urmia, Iran.
*Corresponding author: Drmnkh76@gmail.com; ghasemnejad.m@umsu.ac.ir
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No. 07 DOI: 10.1186/s11658-021-00305-5 Volume 27 (2022) - 27:07
Authors Hongjuan You1†, Qi Li1,2†, Delong Kong1, Xiangye Liu1, Fanyun Kong1*, Kuiyang Zheng1,3 and Renxian Tang1,3*
Abstract Canonical Wnt/β-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a signifcant protein modifcation which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classifed into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modifcation, and it can modulate the transcription of important biological molecules in Wnt/β-catenin signaling. Additionally, as a type of post-translational modifcation, non-histone acetylation directly alters the function of the core molecules in Wnt/β-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/β-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/β-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling.
Keywords Protein lysine acetylation, Canonical Wnt/β-catenin signaling, Interaction, Therapy, Molecular mechanisms
Address and Contact Information 1 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
2 Laboratory Department, The People’s Hospital of Funing, Yancheng, Jiangsu, China.
3 National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
*Corresponding author: kong.fanyun@163.com; tangrenxian-t@163.com
Hongjuan You and Qi Li contributed equally to this work
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No. 08 DOI: 10.1186/s11658-022-00306-y Volume 27 (2022) - 27:08
Authors Zhiguo Luo1†, Qing Hu2†, Yuanhui Tang1, Yahui Leng2, Tian Tian2, Shuangyue Tian2, Chengyang Huang2, Ao Liu2, Xinzhou Deng1* and Li Shen1,2*
Abstract Background: Glycosyltransferases play a crucial role in various cancers. β1, 3-N-acetyl-glucosaminyltransferase 2, a polylactosamine synthase, is an important member of the glycosyltransferase family. However, the biological function and regulatory mechanism of β3GNT2 in esophageal carcinoma (ESCA) is still poorly understood.
Methods: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for gene expression and prognosis analysis. Quantitative real-time PCR, Western blot, and immunohistochemistry were performed to detect the expression of β3GNT2 in ESCA cell lines and tissues. In vitro assays and xenograft tumor models were utilized to evaluate the impact of β3GNT2 on ESCA progression. The downstream efectors and upstream regulators of β3GNT2 were predicted by online software and verifed by functional experiments.
Results: We found that β3GNT2 was highly expressed in ESCA tissues and positively correlated with poor prognosis in ESCA patients. β3GNT2 expression was closely associated with the tumor size, TNM stage, and overall survival of ESCA patients. Functionally, β3GNT2 promoted ESCA cell growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Mechanistically, β3GNT2 knockdown decreased the expression of the polylactosamine on EGFR. Knockdown of β3GNT2 also inhibited the JAK/STAT signaling pathway. Meanwhile, the JAK/STAT inhibitor could partly reverse the biological efects caused by β3GNT2 overexpression. Moreover, β3GNT2 expression was positively regulated by CREB1 and negatively regulated by miR-133b. Both CREB1 and miR-133b was involved in the β3GNT2-mediated ESCA progression.
Conclusions: Our study, for the frst time, reveals the importance of β3GNT2 in ESCA progression and ofers a potential therapeutic target for ESCA.
Keywords Esophageal carcinoma, Progression, Glycosyltransferase, β3GNT2
Address and Contact Information 1 Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, Hubei, China
2 Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
*Corresponding author: 576700586@qq.com; 20101061@hbmu.edu.cn
Zhiguo Luo and Qing Hu contributed equally to this article
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No. 09 DOI: 10.1186/s11658-022-00307-x Volume 27 (2022) - 27:09
Authors M. Kanmalar1, Siti Fairus Abdul Sani1*, Nur Izzahtul Nabilla B. Kamri1, Nur Akmarina B. M. Said2, Amirah Hajirah B. A. Jamil2, S. Kuppusamy3, K. S. Mun4 and D. A. Bradley5,6
Abstract Bladder cancer is the fourth most common malignancy in males. It can present across the whole continuum of severity, from mild through well-diferentiated disease to extremely malignant tumours with poor survival rates. As with other vital organ malignancies, proper clinical management involves accurate diagnosis and staging. Chemotherapy consisting of a cisplatin-based regimen is the mainstay in the management of muscle-invasive bladder cancers. Control via cisplatin-based chemotherapy is threatened by the development of chemoresistance. Intracellular cholesterol biosynthesis in bladder cancer cells is considered a contributory factor in determining the chemotherapy response. Farnesyl-diphosphate farnesyltransferase 1 (FDFT1), one of the main regulatory components in cholesterol biosynthesis, may play a role in determining sensitivity towards chemotherapy compounds in bladder cancer. FDFT1-associated molecular identifcation might serve as an alternative or appendage strategy for early prediction of potentially chemoresistant muscle-invasive bladder cancer tissues. This can be accomplished using Raman spectroscopy. Developments in the instrumentation have led to it becoming one of the most convenient forms of analysis, and there is a highly realistic chance that it will become an efective tool in the pathology lab. Chemosensitive bladder cancer tissues tend to have a higher lipid content, more protein genes and more cholesterol metabolites. These are believed to be associated with resistance towards bladder cancer chemotherapy. Herein, Raman peak assignments have been tabulated as an aid to indicating metabolic changes in bladder cancer tissues that are potentially correlated with FDFT1 expression.
Keywords Bladder cancer, Diagnostic, FDFT1, Cisplatin chemoresistance, Raman spectroscopy
Address and Contact Information 1 Department of Physics, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
2 Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia.
3 Department of Surgery, University of Malaya, 50603 Kuala Lumpur, Malaysia.
4 Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
5 Centre for Applied Physics and Radiation Technologies, Sunway University, Jalan University, 46150 Petaling Jaya, Malaysia.
6 Department of Physics, University of Surrey, Guildford GU2 7XH, UK.
*Corresponding author: s.fairus@um.edu.my
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No. 10 DOI: 10.1186/s11658-022-00311-1 Volume 27 (2022) - 27:10
Authors Hamidreza Zalpoor1,2,3†, Abdullatif Akbari4†, Azam Samei5, Razieh Forghaniesfdvajani4, Monireh Kamali6, Azadeh Afzalnia6, Shirin Manshouri6, Fatemeh Heidari7, Majid Pornour8, Majid Khoshmirsafa9, Hossein Aazami10 and Farhad Seif2,11*
Abstract The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and fnding a safe therapeutic strategy and efective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinfammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest infammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.
Keywords COVID-19, CNS, Ephrin, Neuropilin-1, P2X7, CD147, Cytokine, Jak, Infammasome, Neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease
Address and Contact Information 1 American Association of Kidney Patients, Tampa, FL, USA.
2 Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran.
3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientifc Education and Research Network (USERN), Tehran, Iran.
5 Department of Laboratory Sciences, School of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
6 Rajaei Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
7 Immunology Department, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran.
8 Department of Oncology, School of Medicine, University of Maryland, Maryland, USA.
9 Department of Immunology, School of Medicine, Iran University of Medical Sciences, Iran, Iran.
10 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
11 Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Enghelab St., Aboureyhan St., Vahid Nazari Crossroad, P17, 1315795613 Tehran, Iran
*Corresponding author: farhad.seif@outlook.com
† Hamidreza Zalpoor and Abdullatif Akbari contributed equally as the first authors
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No. 11 DOI: 10.1186/s11658-022-00314-y Volume 27 (2022) - 27:11
Authors Shenglong Zhu1,2†, Wei Wang1†, Jingwei Zhang3, Siyu Ji1, Zhe Jing1 and Yong Q. Chen1,2,3*
Abstract Background: A comprehensive understanding of the molecular mechanisms of adipogenesis is a critically important strategy for identifying new targets for obesity intervention.
Methods: Transcriptomic and lipidomic approaches were used to explore the functional genes regulating adipogenic diferentiation and their potential mechanism of action in OP9 cells and adipose-derived stem cells. Oil Red O staining was used to detect oil droplets in adipocytes.
Results: RNA sequencing (RNA-seq) showed that Slc25a5 expression was signifcantly upregulated in adipogenic diferentiation. Depletion of Slc25a5 led to the suppressed expression of adipogenesis-related genes, reduced the accumulation of triglycerides, and inhibited PPARγ protein expression. Moreover, the knockdown of Slc25a5 resulted in signifcant reduction of oxidative phosphorylation (OXPHOS) protein expression (ATP5A1, CQCRC2, and MTCO1) and ATP production. The RNA-seq and real-time quantitative polymerase chain reaction (RT–qPCR) results suggested that adipogenic diferentiation is possibly mediated by ERK1/2 phosphorylation, and this hypothesis was confrmed by intervention with PD98059 (an ERK 1/2 inhibitor).
Conclusions: This study indicates that Slc25a5 inhibits adipogenesis and might be a new therapeutic target for the treatment of obesity.
Keywords Obesity, Adipogenic diferentiation, Slc25a5, ERK, Transcriptome, Metabolome
Address and Contact Information 1 Wuxi School of Medicine, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
2 Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi, China.
3 School of Food Science and Technology, Jiangnan University, Wuxi, China.
*Corresponding author: yqc_lab@126.com; yqchen@jiangnan.edu.cn
Shenglong Zhu and Wei Wang contributed equally to this work
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No. 12 DOI: 10.1186/s11658-022-00315-x Volume 27 (2022) - 27:12
Authors Silvia Chichiarelli1*, Fabio Altieri1, Giuliano Paglia1, Elisabetta Rubini1,2, Marco Minacori1 and Margherita Eufemi1
Abstract The ERp57/PDIA3 protein is a pleiotropic member of the PDIs family and, although predominantly located in the endoplasmic reticulum (ER), has indeed been found in other cellular compartments, such as the nucleus or the cell membrane. ERp57/PDIA3 is an important research target considering it can be found in various subcellular locations. This protein is involved in many diferent physiological and pathological processes, and our review describes new data on its functions and summarizes some ligands identifed as PDIA3-specifc inhibitors.
Keywords ERp57, PDIA3, PDI inhibitors, Punicalagin, Vitamin D3, Cancer, Infections, Nervous system, Cardiovascular system, Fertility
Address and Contact Information 1 Department of Biochemical Sciences “A.Rossi-Fanelli”, Sapienza University of Rome, P.le A.Moro 5, 00185 Rome, Italy
2 Enrico Ed Enrica Sovena” Foundation, Rome, Italy.
*Corresponding author: silvia.chichiarelli@uniroma1.it
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No. 13 DOI: 10.1186/s11658-022-00313-z Volume 27 (2022) - 27:
Authors Xiaotian Wang, Yongsheng Song, Yaxing Shi, Da Yang, Jiaxing Li and Bo Yin*
Abstract In recent years, morbidity and mortality of prostate cancer (PCa) have increased dramatically, while mechanistic understanding of its onset and progression remains unmet. LncRNA SNHG3 has been proved to stimulate malignant progression of multiple cancers, whereas its functional mechanism in PCa needs to be deciphered. In this study, our analysis in the TCGA database revealed high SNHG3 expression in PCa tissue. Further analysis in starBase, TargetScan, and mirDIP databases identifed the SNHG3/miR-152-3p/SLC7A11 regulatory axis. FISH was conducted to assess the distribution of SNHG3 in PCa tissue. Dual-luciferase reporter gene and RIP assays confrmed the relationship among the three objects. Next, qRT-PCR and western blot were conducted to measure expression levels of SNHG3, miR-152-3p, and SLC7A11. CCK-8, colony formation, Transwell, and fow cytometry were carried out to assess proliferation, migration, invasion, methionine dependence, apoptosis, and the cell cycle. It was noted that SNHG3 as a molecular sponge of miR-152-3p stimulated proliferation, migration, and invasion, restrained methionine dependence and apoptosis, and afected the cell cycle of PCa cells via targeting SLC7A11. Additionally, we constructed xenograft tumor models in nude mice and confrmed that knockdown of SNHG3 could restrain PCa tumor growth and elevate methionine dependence in vivo. In conclusion, our investigation improved understanding of the molecular mechanism of SNHG3 modulating PCa progression, thereby generating novel insights into clinical therapy for PCa.
Keywords Prostate cancer, SNHG3, miR-152-3p, SLC7A11, Methionine dependence
Address and Contact Information Department of Urology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang 110001, Liaoning, China
*Corresponding author: yinbo19751003@hotmail.com
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No. 14 DOI: 10.1186/s11658-022-00317-9 Volume 27 (2022) - 27:14
Authors Arash Letafati1, Sajad Najaf2, Mehran Mottahedi3, Mohammad Karimzadeh4, Ali Shahini3, Setareh Garousi3, Mohammad Abbasi‐Kolli5, Javid Sadri Nahand6, Seyed Saeed Tamehri Zadeh7, Michael R. Hamblin8, Neda Rahimian9,10*, Mohammad Taghizadieh11* and Hamed Mirzaei12,13*
Abstract MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and diferentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to afect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.
Keywords MicroRNAs, Let-7, Viral infections, Regulatory role
Address and Contact Information 1 Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
2 Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
3 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
4 Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
5 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
6 Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
7 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
8 Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
9 Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
10 Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
11 Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.
12 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran. 13Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
*Corresponding author: rahimian.n@iums.ac.ir; MohammadTaghizadieh@gmail.com; mirzaei-h@kaums.ac.ir; h.mirzaei2002@gmail.com
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No. 15 DOI: 10.1186/s11658-022-00310-2 Volume 27 (2022) - 27:15
Authors Ruolan Zhang1*, Yuming Hao2 and Jinrong Zhang1
Abstract Background: Although long non-coding RNA diferentiation antagonizing non-protein coding RNA (DANCR) has been reported to be involved in atherosclerosis (AS) development, its specifc mechanism remains unclear.
Methods: DANCR expression levels in blood samples of AS patients and oxidized low-density lipoprotein (ox-LDL) treated vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The small interfering RNA targeting DANCR (si-DANCR) was used to silence DANCR expression. Cell viability was assessed by CCK-8 assay. Cell apoptosis was evaluated by fow cytometry. Levels of infammatory cytokines, anti-oxidative enzyme superoxide dismutase (SOD) activity, and malonaldehyde (MDA) were detected by specifc commercial kits. An animal AS model was established to confrm the role of DANCR/microR-214-5p/COX20 (the chaperone of cytochrome c oxidase subunit II COX2) in AS development.
Results: DANCR was signifcantly increased in the blood samples of AS patients and ox-LDL treated VSMCs and HUVECs. DANCR downregulation obviously increased viability and reduced apoptosis of ox-LDL-treated VSMCs and HUVECs. Meanwhile, DANCR downregulation reduced the levels of infammatory cytokines, including interleukin (IL)-6 (IL-6), IL-1beta (IL-1β), IL-6 and tumor necrosis factor (TNF)-alpha (TNF-α) and MDA while increasing the SOD level in ox-LDL-treated VSMCs and HUVECs. DANCR regulated COX20 expression by acting as a competing endogenous RNA (ceRNA) of miR-214-5p. Rescue experiments demonstrated that miR-214-5p downregulation obviously attenuated si-DANCR-induced protective efects on ox-LDL-caused endothelial injury.
Conclusions: Our results revealed that DANCR promoted AS progression by targeting the miR-214-5p/COX20 axis, suggesting that DANCR might be a potential therapeutic target for AS.
Keywords Atherosclerosis, DANCR, miR-214-5p, COX20
Address and Contact Information 1 Department of Cardiology, Harrison International Peace Hospital, No. 180 Renmin Road, Hengshui City 053000, Hebei Province, People’s Republic of China
2 Department of Cardiology, Second Afliated Hospital of Hebei Medical University, Shijiazhuang City 05000, Hebei Province, People’s Republic of China.
*Corresponding author: ruolanzhangharriso@163.com
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No. 16 DOI: 10.1186/s11658-022-00316-w Volume 27 (2022) - 27:16
Authors Boyu Liu1†, Ruixiang Chen1,2†, Jie Wang1†, Yuanyuan Li1†, Chengyu Yin1, Yan Tai3, Huimin Nie1, Danyi Zeng1, Junfan Fang1, Junying Du1, Yi Liang1, Xiaomei Shao1, Jianqiao Fang1* and Boyi Liu1*
Abstract Background: Allergic contact dermatitis (ACD) is a common skin condition characterized by contact hypersensitivity to allergens, accompanied with skin infammation and a mixed itch and pain sensation. The itch and pain dramatically afects patients’ quality of life. However, still little is known about the mechanisms triggering pain and itch sensations in ACD.
Methods: We established a mouse model of ACD by sensitization and repetitive challenge with the hapten oxazolone. Skin pathological analysis, transcriptome RNA sequencing (RNA-seq), qPCR, Ca2+ imaging, immunostaining, and behavioral assay were used for identifying gene expression changes in dorsal root ganglion innervating the infamed skin of ACD model mice and for further functional validations.
Results: The model mice developed typical ACD symptoms, including skin dryness, erythema, excoriation, edema, epidermal hyperplasia, infammatory cell infltration, and scratching behavior, accompanied with development of eczematous lesions. Transcriptome RNA-seq revealed a number of diferentially expressed genes (DEGs), including 1436-DEG mRNAs and 374-DEG-long noncoding RNAs (lncRNAs). We identifed a number of DEGs specifcally related to sensory neuron signal transduction, pain, itch, and neuroinfammation. Comparison of our dataset with another published dataset of atopic dermatitis mouse model identifed a core set of genes in peripheral sensory neurons that are exclusively afected by local skin infammation. We further found that the expression of the pain and itch receptor MrgprD was functionally upregulated in dorsal root ganglia (DRG) neurons innervating the infamed skin of ACD model mice. MrgprD activation induced by its agonist β-alanine resulted in exaggerated scratching responses in ACD model mice compared with naïve mice.
Conclusions: We identifed the molecular changes and cellular pathways in peripheral sensory ganglia during ACD that might participate in neurogenic infammation, pain, and itch. We further revealed that the pain and itch receptor MrgprD is functionally upregulated in DRG neurons, which might contribute to peripheral pain and itch sensitization during ACD. Thus, targeting MrgprD may be an efective method for alleviating itch and pain in ACD.
Keywords Itch, Pain, Sensory neurons, Allergic contact dermatitis, RNA-seq
Address and Contact Information 1 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310053, China.
2 The First Department of Acupuncture, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi, China.
3 Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
*Corresponding author: fangjianqiao7532@163.com; boyi.liu@foxmail.com
Boyu Liu, Ruixiang Chen, Jie Wang and Yuanyuan Li contributed equally to this work
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No. 17 DOI: 10.1186/s11658-022-00309-9 Volume 27 (2022) - 27:17
Authors Le Lu, Jingjing Huang, Jiantao Mo, Xuanbo Da, Qiaoxin Li, Meng Fan and Hongwei Lu*
Abstract Background: Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized.
Methods: The expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confrmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting.
Results: Cancer-associated fbroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive efects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive efects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis.
Conclusions: CAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These fndings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future.
Keywords Long noncoding RNA, Taurine upregulated gene 1, Hepatocellular carcinoma, microRNA, Sine oculis homeobox homolog 1, Exosomes
Address and Contact Information Department of General Surgery, The Second Afliated Hospital of Xi’an Jiaotong University, No.157, West 5th Road, Xi’an 710004, China
*Corresponding author: lhwdoc@163.com; lhwlhw135@163.com
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No. 18 DOI: 10.1186/s11658-022-00323-x Volume 27 (2022) - 27:18
Authors Zuzana Pokorna, Jan Vyslouzil, Borivoj Vojtesek and Philip J. Coates*
Abstract Background: ΔNp63 overexpression is a common event in squamous cell carcinoma (SCC) that contributes to tumorigenesis, making ΔNp63 a potential target for therapy.
Methods: We created inducible TP63-shRNA cells to study the efects of p63-depletion in SCC cell lines and non-malignant HaCaT keratinocytes. DNA damaging agents, growth factors, signaling pathway inhibitors, histone deacetylase inhibitors, and metabolism-modifying drugs were also investigated for their ability to infuence ΔNp63 protein and mRNA levels.
Results: HaCaT keratinocytes, FaDu and SCC-25 cells express high levels of ΔNp63. HaCaT and FaDu inducible TP63-shRNA cells showed reduced proliferation after p63 depletion, with greater efects on FaDu than HaCaT cells, compatible with oncogene addiction in SCC. Genotoxic insults and histone deacetylase inhibitors variably reduced ΔNp63 levels in keratinocytes and SCC cells. Growth factors that regulate proliferation/survival of squamous cells (IGF-1, EGF, amphiregulin, KGF, and HGF) and PI3K, mTOR, MAPK/ERK or EGFR inhibitors showed lesser and inconsistent efects, with dual inhibition of PI3K and mTOR or EGFR inhibition selectively reducing ΔNp63 levels in HaCaT cells. In contrast, the antihyperlipidemic drug lovastatin selectively increased ΔNp63 in HaCaT cells.
Conclusions: These data confrm that ΔNp63-positive SCC cells require p63 for continued growth and provide proof of concept that p63 reduction is a therapeutic option for these tumors. Investigations of ΔNp63 regulation identifed agent-specifc and cell-specifc pathways. In particular, dual inhibition of the PI3K and mTOR pathways reduced ΔNp63 more efectively than single pathway inhibition, and broad-spectrum histone deacetylase inhibitors showed a time-dependent biphasic response, with high level downregulation at the transcriptional level within 24 h. In addition to furthering our understanding of ΔNp63 regulation in squamous cells, these data identify novel drug combinations that may be useful for p63-based therapy of SCC.
Keywords ΔNp63, Oncogene addiction, Squamous cell carcinoma, DNA damage, Histone deacetylase inhibitors, Growth factor signaling
Address and Contact Information Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic
*Corresponding author: philip.coates@mou.cz
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No. 19 DOI: 10.1186/s11658-022-00312-0 Volume 27 (2022) - 27:19
Authors Yi‐Fang Yang1,2†, Chuang‐Ming Wang3†, I.‐Hsin Hsiao1, Yi‐Liang Liu1,4, Wen‐Hao Lin1,4, Chih‐Li Lin4, Hui‐Chih Hung1,6,7* and Guang‐Yaw Liu4,5*
Abstract Peptididylarginine deiminase type 2 (PADI2) catalyzes the conversion of arginine residues to citrulline residues on proteins. We demonstrate that PADI2 induces T cell activation and investigate how PADI2 promotes activated T cell autonomous death (ACAD). In activated Jurkat T cells, overexpression of PADI2 signifcantly increases citrullinated proteins and induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, ultimately resulting in the expression of autophagy-related proteins and autophagy. PADI2 promoted autophagy and resulted in the early degradation of p62 and the light chain 3B (LC3B)-II accumulation. In Jurkat T cells, silencing the autophagy-related gene (Atg) 12 protein inhibits PADI2-mediated autophagy and promotes ER stress and apoptosis, whereas overexpression of Atg12 decreased ER stress and prolonged autophagy to promote cell survival. Additionally, PADI2 regulates T cell activation and the production of Th17 cytokines in Jurkat T cells (interleukins 6, IL-17A, IL-17F, IL-21, and IL-22). In Jurkat T cells, silencing IL-6 promotes autophagy mediated by PADI2 and inhibits PADI2-induced apoptosis, whereas silencing Beclin-1 increases the activation and survival of Th17-like T cells while decreasing autophagy and apoptosis. PADI2 silencing alleviates ER stress caused by PADI2 and decreases cytokine expression associated with Th17-like T cell activation and ACAD. We propose that PADI2 was involved in Th17 lymphocyte ACAD via a mechanism involving ER stress and autophagy that was tightly regulated by PADI2-mediated citrullination. These fndings suggest that inhibiting Th17 T cell activation and the development of severe autoimmune diseases may be possible through the use of novel antagonists that specifcally target PADI2.
Keywords Peptidylarginine deiminase 2, Cytokines, Activated T cell-autonomous death, Endoplasmic reticulum stress, Autophagy
Address and Contact Information 1 Department of Life Sciences, National Chung Hsing University (NCHU), Taichung 40227, Taiwan
2 Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
3 Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital (CYCH), Chia‐Yi 60002, Taiwan.
4 Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
5 Department of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
6 Institute of Genomics and Bioinformatics, National Chung Hsing University (NCHU), Taichung 40227, Taiwan.
7 iEGG and Animal Biotechnology Center, NCHU, Taichung 40227, Taiwan.
*Corresponding author: hchung@dragon.nchu.edu.tw; liugy@csmu.edu.tw
Yi-Fang Yang and Chuang Ming Wang contributed equally to this work
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No. 20 DOI: 10.1186/s11658-022-00319-7 Volume 27 (2022) - 27:20
Authors Donatella Romaniello1,2†, Valerio Gelfo1,2†, Federica Pagano1, Enea Ferlizza1, Michela Sgarzi1,2, Martina Mazzeschi1,2, Alessandra Morselli1, Carmen Miano3, Gabriele D’Uva1,3 and Mattia Lauriola1,2*
Abstract Background: EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of diferent clinical trials show that patients with wild-type KRAS and BRAF beneft from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear.
Methods: Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofuorescence.
Results: In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance.
Conclusions: To sum up, our fndings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.
Keywords EGFR, Pseudo-senescence, IL-1, Cell plasticity, Colon cancer, Cetuximab, Resistance
Address and Contact Information 1 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
2 Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola-Malpighi Polyclinic, 40138 Bologna, Italy.
3 National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy.
*Corresponding author: mattia.lauriola2@unibo.it
Donatella Romaniello and Valerio Gelfo contributed equally to this work.
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No. 21 DOI: 10.1186/s11658-022-00320-0 Volume 27 (2022) - 27:21
Authors Mina Homayoonfal1, Zatollah Asemi1* and Bahman Yousef2,3*
Abstract Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufcient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer treatment has been observed. Bioactive phytochemicals exert their anticancer features through two main ways: they induce cytotoxic efects against cancerous cells without having any detrimental impact on normal cell macromolecules such as DNA and enzymes, while at the same time combating the oncogenic signaling axis activated in tumor cells. Thymoquinone (TQ), the most abundant bioactive compound of Nigella sativa, has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation, along with inducing immune system responses and reducing side efects of traditional chemotherapeutic drugs. The present review is focused on the characteristics and mechanisms by which TQ exerts its cytotoxic efects on bone malignancies.
Keywords Osteosarcoma, Bone metastasis, Thymoquinone, Signaling pathway, Apoptosis, Angiogenesis, Chemotherapy resistance
Address and Contact Information 1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
2 Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
*Corresponding author: Asemi_r@yahoo.com; bahmanusef@gmail.com
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No. 22 DOI: 10.1186/s11658-022-00322-y Volume 27 (2022) - 27:22
Authors Tao Yin* and Haonan Zhao
Abstract Background: miR-152-3p functions as a tumour suppressor in the progression of hepatic tumorigenesis. Herein, we further discussed the prognostic signifcance and immune infltration of miR-152-3p and its potential gene target in hepatocellular carcinoma (HCC).
Methods: The Cancer Genome Atlas (TCGA), Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), Human Protein Atlas (HPA) and Kaplan–Meier Plotter databases were used to evaluate miR-152-3p and roundabout guidance receptor 1 (ROBO1) expression, prognosis and immune infltration. In vitro cell experiments, including cell proliferation and apoptosis, were evaluated using Cell Counting Kit 8 (CCK8) and terminal-deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assays.
Results: Up-regulation of ROBO1 functioned as an oncogene associated with poor prognosis, immune cell enrichment and cell proliferation in HCC. ROBO1 was signifcantly positively correlated with the enrichment of multiple immune cells and their biomarkers. Enrichment of type-2 T-helper (Th2) cells is an unfavourable biomarker of HCC prognosis. GSEA revealed that ROBO1 correlated with apoptosis, mitosis and carcinogenic signalling pathways. Suppression of cell proliferation and the enhancement of cell apoptosis by miR-152-3p mimics were counteracted by overexpression of ROBO1 in HCC cells.
Conclusion: ROBO1 expression is positively correlated with multiple immune checkpoint molecules, suggesting that ROBO1 may be a potential drug target to enhance the potency of immunotherapy. The miR-152-3p/ROBO1 signalling axis contributes to malignant progression and provides a prospective immunotherapeutic target for HCC.
Keywords Roundabout guidance receptor 1, Prognosis, miR-152-3p, Immunotherapy, Hepatic tumorigenesis
Address and Contact Information Department of General Surgery, Afliated Hospital of Chifeng University, No. 42 Wangfu Street, Songshan, Chifeng 024005, China
*Correspondeing author: tao_y717@163.com
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No. 23 DOI: 10.1186/s11658-022-00327-7 Volume 27 (2022) - 27:23
Title ROR2 increases the chemoresistance of melanoma by regulating p53 and Bcl2‐family proteins via ERK hyperactivation
Authors María Victoria Castro1,2, Gastón Alexis Barbero1,2, Paula Máscolo1, Rocío Ramos1, María Josefna Quezada1,2 and Pablo Lopez‐Bergami1,2*
Abstract Background: ROR2 is a tyrosine-kinase receptor whose expression is dysregulated in many human diseases. In cancer, ROR2 stimulates proliferation, survival, migration, and metastasis, and is associated with more aggressive tumor stages. The purpose of this work is to study the role of ROR2 in the chemoresistance of melanoma.
Methods: Gain- and loss-of-function experiments were used to study the biological function of ROR2 in melanoma. Cell death induced by chemotherapeutic drugs and BH-3 mimetics was evaluated using crystal violet cytotoxicity assays and annexin V/propidium iodide staining. Western blots were used to evaluate the expression of proteins implicated in cell death. The diferences observed between cells with manipulation of ROR2 levels and control cells were evaluated using both Student’s t-test and ANOVA.
Results: We describe that ROR2 contributes to tumor progression by enhancing the resistance of melanoma cells to both chemotherapeutic drugs and BH-3 mimetics. We demonstrate that ROR2 reduced cell death upon treatment with cisplatin, dacarbazine, lomustine, camptothecin, paclitaxel, ABT-737, TW-37, and venetoclax. This efect was mediated by the inhibition of apoptosis. In addition, we investigated the molecular mechanisms implicated in this role of ROR2. We identifed the MDM2/p53 pathway as a novel target of ROR2 since ROR2 positively regulates MDM2 levels, thus leading to p53 downregulation. We also showed that ROR2 also upregulates Mcl-1 and Bcl2-xL while it negatively regulates Bax and Bid expression. The efect of ROR2 on the expression of these proteins is mediated by the hyperactivation of ERK.
Conclusions: These results demonstrate that ROR2 contributes to melanoma progression by inhibiting apoptosis and increasing chemoresistance. These results not only position ROR2 as a marker of chemoresistance but also support its use as a novel therapeutic target in cancer.
Keywords ROR2, ERK, Melanoma, Chemoresistance, Apoptosis
Address and Contact Information 1 Centro de Estudios Biomédicos, Básicos, Biotecnológicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Hidalgo 775, 6th Floor, Lab 602, 1405 Buenos Aires, Argentina
2 Consejo Nacional de Investigaciones Científcas y Técnicas (CONICET), 1425 Buenos Aires, Argentina.
*Corresponding author: lopezbergami.pablo@maimonides.edu
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No. 24 DOI: 10.1186/s11658-022-00321-z Volume 27 (2022) - 27:24
Authors Junqiang Li1†, Yang Song1†, Chao Zhang1†, Ronglin Wang1, Lei Hua1, Yongdong Guo1, Dongxue Gan1, Liaoliao Zhu1, Shanshan Li1, Peixiang Ma1, Cheng Yang1, Hong Li1, Jing Yang1, Jingjie Shi1, Xiaonan Liu2* and Haichuan Su1*
Abstract Background: Transmembrane protein 43 (TMEM43), a member of the transmembrane protein subfamily, plays a critical role in the initiation and development of cancers. However, little is known concerning the biological function and molecular mechanisms of TMEM43 in pancreatic cancer.
Methods: In this study, TMEM43 expression levels were analyzed in pancreatic cancer samples compared with control samples. The relationship of TMEM43 expression and disease-free survival (DFS) and overall survival (OS) were assessed in pancreatic cancer patients. In vitro and in vivo assays were performed to explore the function and role of TMEM43 in pancreatic cancer. Coimmunoprecipitation (co-IP) followed by protein mass spectrometry was applied to analyze the molecular mechanisms of TMEM43 in pancreatic cancer.
Results: We demonstrated that TMEM43 expression level is elevated in pancreatic cancer samples compared with control group, and is correlated with poor DFS and OS in pancreatic cancer patients. Knockdown of TMEM43 inhibited pancreatic cancer progression in vitro, decreased the percentage of S phase, and inhibited the tumorigenicity of pancreatic cancer in vivo. Moreover, we demonstrated that TMEM43 promoted pancreatic cancer progression by stabilizing PRPF3 and regulating the RAP2B/ERK axis.
Conclusions: The present study suggests that TMEM43 contributes to pancreatic cancer progression through the PRPF3/RAP2B/ERK axis, and might be a novel therapeutic target for pancreatic cancer.
Keywords Pancreatic cancer, Progression, TMEM43, PRPF3, RAP2B
Address and Contact Information 1 Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi, China
2 Ambulatory Surgery Center, Xijing Hospital, Air Force Medical University, Xi’an 710032, Shaanxi, China
*Correspondence: 15353589999@163.com;suhc@fmmu.edu.cn
Junqiang Li, Yang Song and Chao Zhang contributed equally to this work
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No. 25 DOI: 10.1186/s11658-022-00326-8 Volume 27 (2022) - 27:25
Authors Xing Zeng, Zhiquan Hu, Yuanqing Shen, Xian Wei, Jiahua Gan and Zheng Liu*
Abstract Background: Accumulating evidence indicates that miR-5195-3p exerts tumor-suppressive roles in several tumors. However, the clinical signifcance and biological function of miR-5195-3p in prostate cancer (PCa) have not been reported yet.
Methods: The expression levels of miR-5195-3p and Cyclin L1 (CCNL1) were determined using quantitative real-time PCR in clinical specimens and cell lines. The clinical signifcance of miR-5195-3p in patients with PCa was evaluated using Kaplan–Meier survival analysis and Cox regression models. Cell proliferation and cell cycle distribution were measured by CCK-8 assay and fow cytometry, respectively. The association between miR-5195-3p and CCNL1 was analyzed by luciferase reporter assay.
Results: MiR-5195-3p expression levels were signifcantly downregulated in 69 paired PCa tissues compared with matched adjacent normal tissues. The decreased miR-5195-3p expression was associated with Gleason score and TNM stage, as well as worse survival prognosis. The in vitro experiments showed that miR-5195-3p overexpression suppressed the proliferation and cell cycle G1/S transition in PC-3 and DU145 cells. Elevated miR-5195-3p abundance obviously impaired tumor formation in vivo using PC-3 xenografts. Mechanistically, CCNL1 was a direct target of miR-5195-3p in PCa cells, which was inversely correlated with miR-5195-3p in PCa tissues. Importantly, CCNL1 knockdown imitated, while overexpression reversed, the efects of miR-5195-3p overexpression on PCa cell proliferation and cell cycle G1/S transition.
Conclusions: Our data suggest that miR-5195-3p functions as a tumor suppressor by targeting CCNL1 in PCa.
Keywords Prostate cancer, miR-5195-3p, CCNL1, Proliferation
Address and Contact Information Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Ave, Wuhan 430030, Hubei, China
*Corresponding author: liu_zheng0205@126.com
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No. 26 DOI: 10.1186/s11658-022-00329-5 Volume 27 (2022) - 27:26
Authors Wenqing Sun1†, Yan Li1†, Dongyu Ma1†, Yi Liu2, Qi Xu1, Demin Cheng1, Guanru Li1 and Chunhui Ni1*
Abstract Background: N6-methyladenosine (m6A) is the most common and abundant internal modifcation of RNA. Its critical functions in multiple physiological and pathological processes have been reported. However, the role of m6A in silica-induced pulmonary fbrosis has not been fully elucidated. AlkB homolog 5 (ALKBH5), a well-known m6A demethylase, is upregulated in the silica-induced mouse pulmonary fbrosis model. Here, we sought to investigate the function of ALKBH5 in pulmonary fbrosis triggered by silica inhalation. Methods: We performed studies with fbroblast cell lines and silica-induced mouse pulmonary fbrosis models. The expression of ALKBH5, miR-320a-3p, and forkhead box protein M1 (FOXM1) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6 A RNA immuno-precipitation assays (MeRIP), western bolt, immunofuorescence assays, and 5-ethynyl-2’-deoxyuridine (EdU) fuorescence staining were performed to explore the roles of ALKBH5, miR-320a-3p, and FOXM1 in fibroblast activation. Results: ALKBH5 expression was increased in silica-inhaled mouse lung tissues and transforming growth factor (TGF)-β1-stimulated fbroblasts. Moreover, ALKBH5 knockdown exerted antifbrotic efects in vitro. Simultaneously, downregulation of ALKBH5 elevated miR-320a-3p but decreased pri-miR-320a-3p. Mechanically, ALKBH5 demethylated pri-miR-320a-3p, thus blocking the microprocessor protein DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p. We further demonstrated that miR-320a-3p could regulate fbrosis by targeting FOXM1 messenger RNA (mRNA) 3′-untranslated region (UTR). Notably, our study also verifed that ALKBH5 could also directly regulate FOXM1 in an m6A-dependent manner. Conclusions: Our fndings suggest that ALKBH5 promotes silica-induced lung fbrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1 directly. Approaches aimed at ALKBH5 may be efcacious in treating lung fbrosis.
Keywords Silicosis, ALKBH5, miR-320a-3p, FOXM1, m6A
Address and Contact Information 1 Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
2 Gusu School, Nanjing Medical University, Nanjing 211166, China.
*Corresponding author: chni@njmu.edu.cn; chninjmu@126.com
Wenqing Sun, Yan Li, and Dongyu Ma contributed equally to this work and should be considered co-frst authors
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No. 27 DOI: 10.1186/s11658-022-00325-9 Volume 27 (2022) - 27:27
Authors Tianyun Gao, Feifei Huang, Wenqing Wang, Yuanyuan Xie and Bin Wang*
Abstract Background: After spinal cord injury (SCI), dysregulated or nonresolving infammatory processes can severely disturb neuronal homeostasis and drive neurodegeneration. Although mesenchymal stromal cell (MSC)-based therapies have showed certain therapeutic efcacy, no MSC therapy has reached its full clinical goal. In this study, we examine interleukin-10 (IL10) genetically modifed clinical-grade MSCs (IL10-MSCs) and evaluate their clinical safety, efectiveness, and therapeutic mechanism in a completely transected SCI mouse model.
Methods: We established stable IL10-overexpressing human umbilical-cord-derived MSCs through electric transduction and screened out clinical-grade IL10-MSCs according to the criteria of cell-based therapeutic products, which were applied to mice with completely transected SCI by repeated tail intravenous injections. Then we comprehensively investigated the motor function, histological structure, and nerve regeneration in SCI mice, and further explored the potential therapeutic mechanism after IL10-MSC treatment.
Results: IL10-MSC treatment markedly reinforced locomotor improvement, accompanied with decreased lesion volume, regeneration of axons, and preservation of neurons, compared with naïve unmodifed MSCs. Further, IL10-MSC transplantation increased the ratio of microglia to infltrated alternatively activated macrophages (M2), and reduced the ratio of classically activated macrophages (M1) at the injured spinal cord, meanwhile increasing the percentage of Treg and Th2 cells, and reducing the percentage of Th1 cells in the peripheral circulatory system. In addition, IL10-MSC administration could prevent apoptosis and promote neuron diferentiation of neural stem cells (NSCs) under infammatory conditions in vitro.
Conclusions: IL10-MSCs exhibited a reliable safety profle and demonstrated promising therapeutic efcacy in SCI compared with naïve MSCs, providing solid support for future clinical application of genetically engineered MSCs.
Keywords MSCs, Interleukin 10, Gene modifcation, Spinal cord injury, Cell-based therapy, Cell quality assessment
Address and Contact Information Center for Clinic Stem Cell Research, the Afliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China
*Corresponding author: wangbin022800@126.com
Tianyun Gao and Feifei Huang contributed equally to this study
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No. 28 DOI: 10.1186/s11658-022-00324-w Volume 27 (2022) - 27:28
Authors Han‐Ming Huang1, Xiao‐Yu Huang1, Shao‐Ping Wu1, Can‐Keng Chen1, Xin‐Hua He2* and Yong‐Fa Zhang1*
Abstract Background: Parecoxib plays an important role in inhibition of human cancer. However, the efect of parecoxib on esophageal squamous cell carcinoma (ESCC) is still not well known. The purpose of this study was to investigate the efect of parecoxib on ESCC and its underlying mechanism.
Methods: RNA-sequence analysis was performed to identify functional alterations and mechanisms. Cell cycle, proliferation, invasion, and migration were assessed using fow cytometry, CCK-8 assay, colony formation, transwell, and wound healing assays. Extracellular matrix (ECM) degradation was detected by substrate gel zymography and 3D cell culture assay. Western blotting was used to detect parecoxib-dependent mechanisms involving cell cycle, proliferation, invasion, and migration. Tumor formation in vivo was detected by mouse assay.
Results: Functional experiments indicated that parecoxib induced ESCC cell cycle arrest in G2 phase, and inhibited cell proliferation, invasion, and migration in vitro. Western blotting revealed that parecoxib downregulated the phosphorylation levels of AKT and PDK1, as well as the expression of the mutant p53, cyclin B1, and CDK1, while upregulating p21waf1. Parecoxib inhibited matrix metalloproteinase-2 (MMP2) secretion and invadopodia formation, which were related to ECM degradation. Furthermore, we found that parecoxib suppressed ESCC growth in heterotopic tumor models.
Conclusion: Parecoxib inhibits ESCC progression, including cell cycle, proliferation, invasion, and migration, via the PDK1–AKT signaling pathway.
Keywords Parecoxib, Mutant p53, PDK1–AKT, ESCC
Address and Contact Information 1 Department of Anesthesiology, Second Afliated Hospital of Shantou University Medical College, Shantou 515041, People’s Republic of China
2 Department of Physiology, Shantou University Medical College, Shantou 515041, People’s Republic of China
*Corresponding author: Hexh@stu.edu.cn; 10yfzhang1@stu.edu.cn
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No. 29 DOI: 10.1186/s11658-022-00318-8 Volume 27 (2022) - 27:29
Authors Jin Li1,2†, Shi‐hua Deng1,2†, Jing Li1,2†, Li Li1,2, Feng Zhang1,2, Ye Zou1,2, Dong‐ming Wu1,2* and Ying Xu1,2*
Abstract Background: Acute lung injury (ALI) has received considerable attention in the feld of intensive care as it is associated with a high mortality rate. Obacunone (OB), widely found in citrus fruits, is a natural bioactive compound with anti-infammatory and antioxidant activities. However, it is not clear whether OB protects against lipopolysaccharide (LPS)-induced ALI. Therefore, in this study, we aimed to evaluate the protective efects of OB and the potential mechanisms against LPS-induced ALI and BEAS-2B cell injury.
Methods: We established a model of BEAS-2B cell injury and a mouse model of ALI by treating with LPS. Samples of in vitro model were subjected to cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release assays. The total number of cells and neutrophils, protein content, and levels of IL-6, TNF-α, and IL-1β were determined in bronchoalveolar lavage fuid (BALF). Glutathione, reactive oxygen species, and malondialdehyde levels were determined in lung tissue. Additionally, immunohistochemical analysis, immunofuorescence, western blot, quantitative real-time PCR, and enzymelinked immunosorbent assay were conducted to examine the efects of OB. Furthermore, mice were treated with an Nrf2 inhibitor (ML385) to verify its role in ferroptosis. Data were analyzed using one-way analysis of variance or paired t-tests.
Results: Compared with the LPS group, OB efectively alleviated LPS-induced ALI by decreasing lung wet/dry weight ratio, reactive oxygen species and malondialdehyde production, and superoxide dismutase and glutathione consumption in vivo. In addition, OB signifcantly alleviated lung histopathological injury, reduced infammatory cytokine secretion and Fe2+ and 4-HNE levels, and upregulated GPX4, SLC7A11, and Nrf2 expression. Mechanistically, OB activated Nrf2 by inhibiting Nrf2 ubiquitinated proteasome degradation. ML385 reversed the protective efects of OB against LPS-induced ALI.
Conclusion: Overall, OB alleviates LPS-induced ALI, making it a potential novel protective agent against LPS-induced ALI.
Keywords Obacunone, Nrf2, Ferroptosis, Acute lung injury, Lipopolysaccharide
Address and Contact Information 1 The First Afliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, People’s Republic of China.
2 School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, People’s Republic of China.
*Corresponding author: harvey1989@126.com; yingxu825@126.com
Jin Li, Shi-hua Deng, and Jing Li contributed equally to this work and share first authorship
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No. 30 DOI: 10.1186/s11658-022-00328-6 Volume 27 (2022) - 27:30
Authors Fei Wang1†, Wenting Hou1†, Xue Li1, Lihong Lu1, Ting Huang1, Minmin Zhu1,2* and Changhong Miao3*
Abstract Objective: Diabetic nephropathy (DN) is regarded as the main vascular complication of diabetes mellitus, directly afecting the outcome of diabetic patients. Infammatory factors were reported to participate in the progress of DN. Wingless-type family member 5 (WNT5A), myeloid zinc fnger 1 (MZF1), and lysine methyltransferase 8 (SETD8) have also been reported to elevate infammatory factor levels and activate the nuclear factor kappa B (NF-κB) pathway to induce endothelial dysfunction. In the current study, it was assumed that MZF1 associates with SETD8 to regulate WNT5A transcription, thus resulting in hyperglycemia-induced glomerular endothelial infammation in DN.
Methods: The present study recruited 25 diagnosed DN patients (type 2 diabetes) and 25 control participants (nondiabetic renal cancer patients with normal renal function, stage I–II) consecutively. Moreover, a DN rat and cellular model was constructed in the present study. Immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR) were implemented to determine protein and messenger RNA (mRNA) levels. Coimmunoprecipitation (CoIP) and immunofuorescence were implemented in human glomerular endothelial cells (HGECs). Chromatin immunoprecipitation assays and dual luciferase assays were implemented to determine transcriptional activity.
Results: The results of this study indicated that levels of WNT5A expression, p65 phosphorylation (p-p65), and infammatory factors were all elevated in DN patients and rats. In vitro, levels of p-p65 and infammatory factors increased along with the increase of WNT5A expression in hyperglycemic HGECs. Moreover, high glucose increased MZF1 expression and decreased SETD8 expression. MZF1 and SETD8 inhibit each other under the stimulus of high glucose, but cooperate to regulate WNT5A expression, thus infuencing p-p65 and endothelial infammatory factors levels. Overexpression of MZF1 and silencing of SETD8 induced endothelial p-p65 and infammatory factors levels, which can be reversed by si-WNT5A. Mechanistic research indicated that MZF1, SETD8, and its downstream target histone H4 lysine 20 methylation (H4K20me1) all occupied the WNT5A promoter region. sh-SETD8 expanded the enrichment of MZF1 on WNT5A promoter. Our in vivo study proved that SETD8 overexpression inhibited levels of WNT5A, p-p65 expression, and infammatory factors in DN rats.
Conclusions: MZF1 links with SETD8 to regulate WNT5A expression in HGECs, thus elevating levels of hyperglycemia-mediated infammatory factors in glomerular endothelium of DN patients and rats.
Keywords Diabetic nephropathy, SETD8, Endothelial
Address and Contact Information 1 Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
2 Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China.
3 Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
*Corresponding author: zhu_mm@126.com; miao_chh@126.com
Fei Wang and Wenting Hou contributed equally to this work
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No. 31 DOI: 10.1186/s11658-022-00330-y Volume 27 (2022) - 27:31
Authors Bo Liu and Kai Guo*
Abstract Background: Circular RNA (circRNA) has been shown to play an important role in a variety of cardiovascular diseases, including myocardial infarction (MI). However, the role of circRbms1 in MI progression remains unclear.
Methods: An MI mouse model was constructed in vivo, and cardiomyocytes were cultured under hypoxia condition to induce a cardiomyocyte injury model in vitro. The expression levels of circRbms1, microRNA (miR)-742-3p, and forkhead box O1 (FOXO1) were determined by quantitative real-time PCR. Cell viability, migration, invasion, and apoptosis were measured using Cell Counting Kit-8 assay, transwell assay, and flow cytometry. Meanwhile, western blot analysis was used to examine the protein levels of apoptosis markers and FOXO1. Additionally, dual-luciferase reporter assay, RNA pull-down assay, and RIP assay were employed to verify the interactions between miR-742-3p and circRbms1 or FOXO1.
Results: CircRbms1 was upregulated in the heart tissues of MI mice and hypoxia-induced cardiomyocytes. Hypoxia induced cardiomyocyte injury by suppressing cell viability, migration, and invasion, and promoting apoptosis. Function experiments showed that circRbms1 overexpression aggravated hypoxia-induced cardiomyocyte injury, while its silencing relieved cardiomyocyte injury induced by hypoxia. Furthermore, circRbms1 sponged miR-742-3p. MiR-742-3p overexpression alleviated hypoxia-induced cardiomyocyte injury, and its inhibitor reversed the suppressive efect of circRbms1 silencing on hypoxia-induced cardiomyocyte injury. Further experiments showed that FOXO1 was a target of miR-742-3p, and its expression was positively regulated by circRbms1. The inhibitory efect of miR-742-3p on hypoxia-induced cardiomyocyte injury was reversed by FOXO1 overexpression.
Conclusion: CircRbms1 regulated the miR-742-3p/FOXO1 axis to mediate hypoxia-induced cardiomyocyte injury, suggesting that circRbms1 might be an efective target for MI treatment.
Keywords Myocardial infarction, Hypoxia, CircRbms1, MiR-742-3p, FOXO1
Address and Contact Information Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665 Kongjiang Road, 20092 Shanghai, China
*Corresponding: guokai@xinhuamed.com.cn
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No. 32 DOI: 10.1186/s11658-022-00334-8 Volume 27 (2022) - 27:32
Authors Alena Gschwind1,2†, Christian Marx3†, Marie D. Just1,2, Paula Severin1,2, Hannah Behring1,2, Lisa Marx‐Blümel1,2, Sabine Becker1,2, Linda Rothenburger3, Martin Förster4, James F. Beck1 and Jürgen Sonnemann1,2,5*
Abstract Background: Autophagy plays an essential role in maintaining cellular homeostasis and in the response to cellular stress. Autophagy is also involved in cell cycle progression, yet the relationship between these processes is not clearly defned.
Results: In exploring this relationship, we observed that the inhibition of autophagy impaired the G2/M phase-arresting activity of etoposide but enhanced the G1 phase-arresting activity of palbociclib. We further investigated the connection of basal autophagy and cell cycle by utilizing the autophagosome tracer dye Cyto-ID in two ways. First, we established a double-labeling fow-cytometric procedure with Cyto-ID and the DNA probe DRAQ5, permitting the cell cycle phase-specifc determination of autophagy in live cells. This approach demonstrated that diferent cell cycle phases were associated with diferent autophagy levels: G1-phase cells had the lowest level, and G2/M-phase cells had the highest one. Second, we developed a fow-cytometric cell-sorting procedure based on Cyto-ID that separates cell populations into fractions with low, medium, and high autophagy. Cell cycle analysis of Cyto-ID-sorted cells confrmed that the high-autophagy fraction contained a much higher percentage of G2/M-phase cells than the low-autophagy fraction. In addition, Cyto-ID-based cell sorting also proved to be useful for assessing other autophagy-related processes: extracellular fux analysis revealed metabolic diferences between the cell populations, with higher autophagy being associated with higher respiration, higher mitochondrial ATP production, and higher glycolysis.
Conclusion: This work provides clear evidence of high autophagy in G2/M-phase cells by establishing a novel cell sorting technique based on Cyto-ID.
Keywords Autophagy, Cell cycle, Cell sorting, Cyto-ID, DRAQ5, Metabolic analysis
Address and Contact Information 1 Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany.
2 Research Center Lobeda, Jena University Hospital, 07747 Jena, Germany.
3 Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07747 Jena, Germany.
4 Clinic of Internal Medicine I, Jena University Hospital, 07747 Jena, Germany.
5 Klinik für Kinder und Jugendmedizin, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany.
*Corresponding author: juergen.sonnemann@med.uni-jena.de
Alena Gschwind and Christian Marx have contributed equally to this work
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No.  33DOI: 10.1186/s11658-022-00332-w Volume 27 (2022) - 27:33
Authors Mohsen Karami Fath1, Kimiya Babakhaniyan2, Maryam Zokaei3,4, Azadeh Yaghoubian5, Sadaf Akbari6, Mahdieh Khorsandi7, Asma Soof8, Mohsen Nabi‐Afadi9, Hamidreza Zalpoor10,11,12, Fateme Jalalifar16, Ali Azargoonjahromi13, Zahra Payandeh14* and Armina Alagheband Bahrami15*
Abstract Background: Nowadays, conventional medical treatments such as surgery, radiotherapy, and chemotherapy cannot cure all types of cancer. A promising approach to treat solid tumors is the use of tumor-targeting peptides to deliver drugs or active agents selectively.
Result: Introducing benefcial therapeutic approaches, such as therapeutic peptides and their varied methods of action against tumor cells, can aid researchers in the discovery of novel peptides for cancer treatment. The biomedical applications of therapeutic peptides are highly interesting. These peptides, owing to their high selectivity, specifcity, small dimensions, high biocompatibility, and easy modifcation, provide good opportunities for targeted drug delivery. In recent years, peptides have shown considerable promise as therapeutics or targeting ligands in cancer research and nanotechnology.
Conclusion: This study reviews a variety of therapeutic peptides and targeting ligands in cancer therapy. Initially, three types of tumor-homing and cell-penetrating peptides (CPPs) are described, and then their applications in breast, glioma, colorectal, and melanoma cancer research are discussed.
Keywords Peptide-based strategies, Tumor-homing peptides, Drug delivery, Targeted delivery
Address and Contact Information 1 Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
2 Department of Medical Surgical Nursing, School of Nursing and Midwifery, Iran University of Medical Sciences, Tehran, Iran.
3 Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
4 Department of Veterinary Medicine, Beyza Branch, Islamic Azad University, Beyza, Iran.
5 Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
6 Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
7 Department of Biotechnology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
8 Department of Physical Chemistry, School of Chemistry, College of Sciences, University of Tehran, Tehran, Iran.
9 Department of Biochemistry, Faculty of biological science, Tarbiat Modares University, Tehran, Iran.
10 American Association of Kidney Patients, Tampa, FL, USA.
11 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
12 Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientifc Education & Research Network (USERN), Tehran, Iran.
13 Shiraz University of Medical Sciences, Shiraz, Iran.
14 Department Medical Biochemistry and Biophysics, Division Medical Infammation Research, Karolinska Institute, Stockholm, Sweden
15 Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
16 School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran. *Corresponding author: zpayandeh58@yahoo.com; aarminaa@gmail.com
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No.  34DOI: 10.1186/s11658-022-00335-7 Volume 27 (2022) - 27:34
Authors Shankun Zhao1†, Weizhou Wu2†, Xuezheng Lin3†, Maolei Shen1, Zhenyu Yang3, Sicong Yu3 and Yu Luo3*
Abstract Vital organ injury is one of the leading causes of global deaths. Accumulating studies have demonstrated that dexmedetomidine (DEX) has an outstanding protective efect on multiple organs for its antiinfammatory and antiapoptotic properties, while the underlying molecular mechanism is not clearly understood. Autophagy, an adaptive catabolic process, has been found to play a crucial role in the organ-protective efects of DEX. Herein, we present a frst attempt to summarize all the evidence on the proposed roles of autophagy in the action of DEX protecting against vital organ injuries via a comprehensive review. We found that most of the relevant studies (17/24, 71%) demonstrated that the modulation of autophagy was inhibited under the treatment of DEX on vital organ injuries (e.g. brain, heart, kidney, and lung), but several studies suggested that the level of autophagy was dramatically increased after administration of DEX. Albeit not fully elucidated, the underlying mechanisms governing the roles of autophagy involve the antiapoptotic properties, inhibiting infammatory response, removing damaged mitochondria, and reducing oxidative stress, which might be facilitated by the interaction with multiple associated genes (i.e., hypoxia inducible factor-1α, p62, caspase-3, heat shock 70 kDa protein, and microRNAs) and signaling cascades (i.e., mammalian target of rapamycin, nuclear factor-kappa B, and c-Jun N-terminal kinases pathway). The authors conclude that DEX hints at a promising strategy in the management of vital organ injuries, while autophagy is crucially involved in the protective efect of DEX.
Keywords Dexmedetomidine (DEX), Autophagy, Organ injury, Protection, Mechanism
Address and Contact Information 1 Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, Zhejiang, China.
2 Department of Urology, Maoming People’s Hospital, Maoming 525000, Guangdong, China.
3 Department of Anesthesia Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
*Corresponding author: luoy@tzzxyy.com
Shankun Zhao, Weizhou Wu, and Xuezheng Lin contributed equally to this work
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No.  35DOI: 10.1186/s11658-022-00336-6 Volume 27 (2022) - 27:35
Authors Sadegh Shojaei Baghini1, Zhanna R. Gardanova2, Saeme Azizi Hassan Abadi3, Burhan Abdullah Zaman4, Ahmet İlhan5, Navid Shomali6, Ali Adili7,8, Roozbeh Moghaddar9*† and Amirhossein Fakhre Yaseri10*†
Abstract The progress of genetic engineering in the 1970s brought about a paradigm shift in genome editing technology. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system is a fexible means to target and modify particular DNA sequences in the genome. Several applications of CRISPR/Cas9 are presently being studied in cancer biology and oncology to provide vigorous site-specifc gene editing to enhance its biological and clinical uses. CRISPR’s flexibility and ease of use have enabled the prompt achievement of almost any preferred alteration with greater efciency and lower cost than preceding modalities. Also, CRISPR/Cas9 technology has recently been applied to improve the safety and efcacy of chimeric antigen receptor (CAR)-T cell therapies and defeat tumor cell resistance to conventional treatments such as chemotherapy and radiotherapy. The current review summarizes the application of CRISPR/Cas9 in cancer therapy. We also discuss the present obstacles and contemplate future possibilities in this context.
Keywords Genome editing, Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated protein 9 (Cas9), Cancer treatment
Address and Contact Information 1 Plant Biotechnology Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
2 Department of Psychotherapy, Pirogov Russian National Research Medical University, 1 Ostrovityanova St., 117997 Moscow, Russia.
3 Department of Nursery and Midwifery, Faculty of Laboratory Science, Islamic Azad University of Chalous, Mazandaran, Iran.
4 Basic Sciences Department, College of Pharmacy, University of Duhok, Kurdistan Region, Iraq.
5 Department of Medical Biochemistry, Faculty of Medicine, Cukurova University, Adana, Turkey.
6 Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran.
7 Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran.
8 Senior Adult Oncology Department, Moftt Cancer Center, University of South Florida, Tampa, USA.
9 Department of Pediatric Hematology and Oncology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
10 Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
*Corresponding author: moghaddarroozbeh@gmail.com; R_moghaddar@yahoo.com; Ahfyaseri@gmail.com
Roozbeh Moghaddar and Amirhossein Fakhre Yaseri contributed equally to this work
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No.  36DOI: 10.1186/s11658-022-00337-5 Volume 27 (2022) - 27:36
Authors Chengwu Xiao, Wei Zhang, Meimian Hua, Huan Chen, Bin Yang, Ye Wang and Qing Yang*
Abstract Background: RING fnger protein 7 (RNF7) is a highly conserved protein that functions as an E3 ubiquitin ligase. RNF7 overexpression is indicated in multiple human cancers, but its role in renal cell carcinoma (RCC) and the mechanisms underlying how it regulates the initiation and progression of RCC have not been explored.
Methods: Bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot were conducted to determine the expression of RNF7 in RCC tissues and cell lines. Knockdown and overexpression experiments were performed to examine the efects of RNF7 on cell viability, apoptosis, and glycolysis in vitro and on tumor growth in nude mice in vivo.
Results: The elevated RNF7 expression in tumor tissues of patients with RCC was correlated with poor survival. RNF7 overexpression inhibited apoptosis and promoted glycolysis in vitro and increased tumor growth in vivo by activating the JAK/STAT3 signaling pathway by ubiquitination of SOCS1. Moreover, RNF7 overexpression afected the sensitivity of RCC cells to sunitinib. Finally, STAT3 activation was necessary for transcriptional induction of RNF7.
Conclusion: These results demonstrate that RNF7 inhibited apoptosis, promoted glycolysis, and inhibited sunitinib sensitivity in RCC cells via ubiquitination of SOCS1, thus activating STAT3 signaling. These suggest the potential for targeting the RNF7-SOCS1/JAK/STAT3 pathway for RCC treatment.
Keywords Apoptosis, Clear cell renal cell carcinoma, Glycolysis, JAK/STAT3, RNF7, SOCS1
Address and Contact Information *Corresponding author: yangqchsmmu@163.com Department of Urology, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Yangpu, Shanghai 200433, China
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No.  37DOI: 10.1186/s11658-022-00338-4 Volume 27 (2022) - 27:37
Authors Mohsen Nabi‐Aadi1†, Morteza Heydari2†, Hamidreza Zalpoor3,4,5, Ibrahim Arman6, Arezoo Sadoughi7, Parisa Sahami8 and Safiyeh Aghazadeh9*
Abstract In nature, lectins are widely dispersed proteins that selectively recognize and bind to carbohydrates and glycoconjugates via reversible bonds at specific binding sites. Many viral diseases have been treated with lectins due to their wide range of structures, specificity for carbohydrates, and ability to bind carbohydrates. Through hemagglutination assays, these proteins can be detected interacting with various carbohydrates on the surface of cells and viral envelopes. This review discusses the most robust lectins and their rationally engineered versions, such as lectibodies, as antiviral proteins. Fusion of lectin and antibody’s crystallizable fragment (Fc) of immunoglobulin G (IgG) produces a molecule called a “lectibody” that can act as a carbohydrate-targeting antibody. Lectibodies can not only bind to the surface glycoproteins via their lectins and neutralize and clear viruses or infected cells by viruses but also perform Fc-mediated antibody efector functions. These functions include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP). In addition to entering host cells, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein S1 binds to angiotensin-converting enzyme 2 (ACE2) and downregulates it and type I interferons in a way that may lead to lung disease. The SARS-CoV-2 spike protein S1 and human immunodeficiency virus (HIV) envelope are heavily glycosylated, which could make them a major target for developing vaccines, diagnostic tests, and therapeutic drugs. Lectibodies can lead to neutralization and clearance of viruses and cells infected by viruses by binding to glycans located on the envelope surface (e.g., the heavily glycosylated SARS-CoV-2 spike protein).
Keywords Lectins, Lectibody, Carbohydrates, Virus envelope, SARS-CoV-2, HIV, EBV, HCV
Address and Contact Information 1 Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
2 Institute of Bio‐chemistry and Biophysics, University of Tehran, Tehran 13145‐1384, Iran.
3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
5 American Association of Kidney Patients, Tampa, FL, USA.
6 Department of Molecular Biology and Genetics, Faculty of Sciences and Arts, Zonguldak Bulent Ecevit University, Zonguldak, Turkey.
7 Department of Immunology, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
8 Medical Biology Research Center, Health Technologies Institute, Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran.
9 Division of Biochemistry, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia 5756151818, Iran.
*Corresponding author: s.aghazadeh@urmia.ac.ir
Mohsen Nabi-Aadi and Morteza Heydari contributed equally to this work as first authors
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No.  38DOI: 10.1186/s11658-022-00339-3 Volume 27 (2022) - 27:38
Authors Armina Alagheband Bahrami1†, Ali Azargoonjahromi2†, Samin Sadraei3, Aryan Aarabi3, Zahra Payandeh4* and Masoumeh Rajabibazl5*
Abstract Designing and producing an efective vaccine is the best possible way to reduce the burden and spread of a disease. During the coronavirus disease 2019 (COVID-19) pandemic, many large pharmaceutical and biotechnology companies invested a great deal of time and money in trying to control and combat the disease. In this regard, due to the urgent need, many vaccines are now available earlier than scheduled. Based on their manufacturing technology, the vaccines available for COVID-19 (severe acute respiratory syndrome coronavirus 2 (SAR-CoV2)) infection can be classifed into four platforms: RNA vaccines, adenovirus vector vaccines, subunit (protein-based) vaccines, and inactivated virus vaccines. Moreover, various drugs have been deemed to negatively afect the progression of the infection via various actions. However, adaptive variants of the SARS-CoV-2 genome can alter the pathogenic potential of the virus and increase the difculty of both drug and vaccine development. In this review, along with drugs used in COVID-19 treatment, currently authorized COVID-19 vaccines as well as variants of the virus are described and evaluated, considering all platforms.
Keywords SARS-CoV-2, COVID-19 pandemic, Prophylactic vaccines, Platform, Vaccination
Address and Contact Information 1 Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2 Shiraz University of Medical Sciences, Shiraz, Iran.
3 Shahid Beheshti University of Medical Sciences, Tehran, Iran.
4 Department Medical Biochemistry and Biophysics, Division Medical Infammation Research, Karolinska Institute, Stockholm, Sweden.
5 Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
*Corresponding author: zahra.payandeh@ki.se; rajabibazl_m@yahoo.com
Armina Alagheband Bahrami and Ali Azargoonjahromi contributed equally to this work.
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No.  39DOI: 10.1186/s11658-022-00331-x Volume 27 (2022) - 27:39
Authors Jinfeng Zhang, Xiaodong Ling, Chengyuan Fang and Jianqun Ma*
Abstract Background: Esophageal squamous cell carcinoma (ESCC) is correlated with worse clinical prognosis and lacks available targeted therapy. Thus, identifcation of reliable biomarkers is required for the diagnosis and treatment of ESCC.
Methods: We downloaded the GSE53625 dataset as a training dataset to screen differentially expressed RNAs (DERs) with the criterion of false discovery rate (FDR)<0.05 and |log2fold change (FC)| >1. A support vector machine classifer was used to find the optimal feature gene set that could conclusively distinguish diferent samples. An eight-lncRNA signature was identifed by random survival forest algorithm and multivariate Cox regression analysis. The RNA sequencing data from The Cancer Genome Atlas (TCGA) database were used for external validation. The predictive value of the signature was assessed using Kaplan–Meier test, time-dependent receiver operating characteristic (ROC) curves, and dynamic area under the curve (AUC). Furthermore, a nomogram to predict patients’ 3-year and 5-year prognosis was constructed. CCK-8 assay, fow cytometry, and transwell assay were conducted in ESCC cells.
Results: A total of 1136 DERs, including 689 downregulated mRNAs, 318 upregulated mRNAs, 74 downregulated lncRNAs and 55 upregulated lncRNAs, were obtained in the GES53625 dataset. From the training dataset, we identifed an eight-lncRNA signature, (ADAMTS9-AS1, DLX6-AS1, LINC00470, LINC00520, LINC01497, LINC01749, MAMDC2-AS1, and SSTR5-AS1). A nomogram based on the eight-lncRNA signature, age, and pathologic stage was developed and showed good accuracy for predicting 3-year and 5-year survival probability of patients with ESCC. Functionally, knockdown of LINC00470 signifcantly suppressed cell proliferation, G1/S transition, and migration in two ESCC cell lines (EC9706 and TE-9). Moreover, knockdown of LINC00470 downregulated the protein levels of PCNA, CDK4, and N-cadherin, while upregulating E-cadherin protein level in EC9706 and TE-9 cells.
Conclusion: Our eight-lncRNA signature and nomogram can provide theoretical guidance for further research on the molecular mechanism of ESCC and the screening of molecular markers.
Keywords Esophageal squamous cell carcinoma, Long noncoding RNA, Signature, Nomogram
Address and Contact Information Department of Thoracic Surgery, Esophagus and Mediastinum, Harbin Medical University Cancer Hospital, No.150 Hapin Road, Harbin 150001, Heilongjiang, China
*Corresponding author: jianqun_ma2016@yeah.net
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No.  40DOI: 10.1186/s11658-022-00340-w Volume 27 (2022) - 27:40
Authors Jian Dong1,2*†, Shuangshuang Li2†, Zilin Lu3†, Pengcheng Du2, Guangqin Liu2, Mintao Li1, Chao Ma1, Jian Zhou2* and Junmin Bao2*
Abstract Background: In patients with acute aortic dissection (AAD), increased vascular smooth muscle cell (VSMC) apoptosis has been found. Human cytomegalovirus (HCMV)-miR-US33-5p was signifcantly increased in the plasma of patients with AAD. However, the roles of miR-US33-5p in human aortic VSMC (HA-VSMC) apoptosis remain to be elucidated.
Methods: In the current study, cell apoptosis was analyzed by fow cytometry, cell proliferation by CCK-8 assay, and diferentially expressed genes by RNA sequencing. Luciferase reporter assay was used for binding analysis between miR-US33-5p and endothelial PAS domain protein 1 (EPAS1), and EPAS1 and amino acid transporter heavy chain, member 2 (SLC3A2). The enrichment degree of SLC3A2 promoter DNA was analyzed by chromatin immunoprecipitation assay. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting were performed for measuring messenger RNA (mRNA) and protein levels, respectively.
Results: It was found that HCMV infection inhibited proliferation but promoted HA-VSMC apoptosis by upregulating HCMV-miR-US33-5p. Transfection of HCMV-miR-US33-5p mimics the signifcant efect on several signaling pathways including integrin signaling as shown in the RNA sequencing data. Western blotting analysis confrmed that HCMV-miR-US33-5p mimics suppression of the activity of key factors of the integrin signal pathway including FAK, AKT, CAS, and Rac. Mechanistic study showed that HCMV-miR-US33-5p bound to the 3′-untranslated region of EPAS1 to suppress its expression, leading to suppression of SLC3A2 expression, which ultimately promoted cell apoptosis and inhibited cell proliferation. This was confrmed by the fndings that silencing EPAS1 signifcantly reduced the SLC3A2 expression and inhibited proliferation and key factors of integrin signal pathway.
Conclusions: HCMV-miR-US33-5p suppressed proliferation, key factors of integrin signal pathway, and EPAS1/SLC3A2 expression, but promoted HA-VSMC apoptosis. These findings highlighted the importance of HCMV-miR-US33-5p/EPAS1/SCL3A2 signaling and may provide new insights into therapeutic strategies for AAD.
Keywords Acute aortic dissection, Aortic vascular smooth muscle cells, Apoptosis, miRNAs, Endothelial PAS domain protein 1, SLC3A2
Address and Contact Information 1 Department of Vascular Surgery, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2 Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai, China.
3 School of Health Science and Engineering, University of Shanghai for Science Technology, Shanghai, China.
*Corresponding author: dr_dongj@163.com; zhoujian1-2@163.com; baojm@189.cn
Jian Dong, Shuangshuang Li, Zilin Lu contributed equally to this work.
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No.  41DOI: 10.1186/s11658-022-00342-8 Volume 27 (2022) - 27:41
Authors Yun‐zhang Dai1, Yong‐da Liu1, Jie Li1, Mei‐ting Chen1, Mei Huang1, Fang Wang1, Qing‐song Yang2*, Ji‐hang Yuan1* and Shu‐han Sun1*
Abstract Background: The molecular mechanisms driving hepatocellular carcinoma (HCC) remain largely unclear. As one of the major epitranscriptomic modifcations, N6-methyladenosine (m6A) plays key roles in HCC. The aim of this study was to investigate the expression, roles, and mechanisms of action of the RNA methyltransferase methyltransferase-like protein 16 (METTL16) in HCC.
Methods: The expression of METTL16 and RAB11B-AS1 was determined by RT-qPCR. The regulation of RAB11B-AS1 by METTL16 was investigated by RNA immunoprecipitation (RIP), methylated RIP (MeRIP), and RNA stability assays. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of METTL16 and RAB11B-AS1.
Results: METTL16 was upregulated in HCC, and its increased expression was correlated with poor prognosis of HCC patients. METTL16 promoted HCC cellular proliferation, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumoral growth in vivo. METTL16 directly bound long noncoding RNA (lncRNA) RAB11B-AS1, induced m6A modifcation of RAB11B-AS1, and decreased the stability of RAB11B-AS1 transcript, leading to the downregulation of RAB11B-AS1. Conversely to METTL16, RAB11B-AS1 is downregulated in HCC, and its decreased expression was correlated with poor prognosis of patients with HCC. Furthermore, the expression of RAB11B-AS1 was negatively correlated with METTL16 in HCC tissues. RAB11B-AS1 repressed HCC cellular proliferation, migration, and invasion, promoted HCC cellular apoptosis, and inhibited HCC tumoral growth in vivo. Functional rescue assays revealed that overexpression of RAB11B-AS1 reversed the oncogenic roles of METTL16 in HCC.
Conclusions: This study identifed the METTL16/RAB11B-AS1 regulatory axis in HCC, which represented novel targets for HCC prognosis and treatment.
Keywords Hepatocellular carcinoma, N6-methyladenosine, RNA methyltransferase, Long noncoding RNA, Tumor progression
Address and Contact Information 1 Department of Medical Genetics, Naval Medical University, Shanghai 200433, China
2 Department of Interventional Radiology, Changhai Hospital, Naval Medical University, Shanghai 20043, China
*Corresponding author: doctoryangqingsong@163.com; jihangyuan@smmu.edu.cn; shsun@vip.sina.com
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No.  42DOI: 10.1186/s11658-022-00341-9 Volume 27 (2022) - 27:42
Authors Lucyna Matusewicz1†, Marlena Golec2†, Aleksander Czogalla1, Kazimierz Kuliczkowski2, Adam Konka2, Joanna Zembala‐John4,5 and Aleksander F. Sikorski3,5*
Abstract The appearance of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its spread all over the world is the cause of the coronavirus disease 2019 (COVID-19) pandemic, which has recently resulted in almost 400 million confrmed cases and 6 million deaths, not to mention unknown long-term or persistent side efects in convalescent individuals. In this short review, we discuss approaches to treat COVID-19 that are based on current knowledge of the mechanisms of viral cell receptor recognition, virus–host membrane fusion, and inhibition of viral RNA and viral assembly. Despite enormous progress in antiviral therapy and prevention, new efective therapies are still in great demand.
Keywords ACE2: coronaviruses, COVID-19, COVID-19 therapies, SARS-CoV-2
Address and Contact Information 1 Department of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, ul. F. Joliot Curie 14a, 50‐383 Wrocław, Poland.
2 Silesian Park of Medical Technology Kardio-Med Silesia, ul. M. Curie‐Skłodowskiej 10c, 41‐800 Zabrze, Poland.
3 Research and Development Centre, Regional Specialist Hospital, Kamieńskiego 73a, 51‐154 Wroclaw, Poland.
4 Chair and Department of Medicine and Environmental Epidemiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, H. Jordana 19, 41‐800 Zabrze, Poland.
5 Acellmed Ltd., M. Curie‐Skłodowskiej 10C, 41‐800 Zabrze, Poland.
*Corresponding author: aleksander.sikorski@wssk.wroc.pl
Lucyna Matusewicz and Marlena Golec participated equally in this work.
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No.  43DOI: 10.1186/s11658-022-00343-7 Volume 27 (2022) - 27:43
Authors Yusheng Huang1†, Lei Xia1†, Xiangwu Tan1†, Jingyi Zhang1, Weiwei Zeng1, Benxu Tan1, Xian Yu1, Wei Fang2* and Zhenzhou Yang1*
Abstract Background: The pivotal role of long noncoding RNAs (lncRNAs) in cancer immune responses has been well established. This study was conducted with the aim of exploring the molecular mechanism of lncRNA small nucleolar RNA host gene 12 (SNHG12) in immune escape of non-small cell lung cancer (NSCLC).
Methods: Expression of lncRNA SNHG12, programmed cell death receptor ligand 1 (PD-L1), ubiquitin-specifc protease 8 (USP8), and human antigen R (HuR) in NSCLC tissues and cells was measured, and their binding relationship was determined. NSCLC cell proliferation and apoptosis were assessed. Peripheral blood mononuclear cells (PBMCs) were co-cultured with NSCLC cells. The ratio of CD8+ T cells, PBMC proliferation, and infammatory factors were determined. lncRNA SNHG12 localization was assessed via subcellular fractionation assay. The half-life period of mRNA was determined using actinomycin D. Xenograft tumor models were established to confrm the role of lncRNA SNHG12 in vivo.
Results: LncRNA SNHG12 was found to be prominently expressed in NSCLC tissues and cells, which was associated with a poor prognosis. Silencing lncRNA SNHG12 resulted in the reduction in proliferation and the promotion of apoptosis of NSCLC cells, while simultaneously increasing PBMC proliferation and the ratio of CD8+ T cells. Mechanically, the binding of lncRNA SNHG12 to HuR improved mRNA stability and expression of PD-L1 and USP8, and USP8-mediated deubiquitination stabilized the protein level of PD-L1. Overexpression of USP8 or PD-L1 weakened the inhibition of silencing lncRNA SNHG12 on the immune escape of NSCLC. Silencing lncRNA SNHG12 restricted tumor growth and upregulated the ratio of CD8+ T cells by decreasing USP8 and PD-L1.
Conclusion: LncRNA SNHG12 facilitated the immune escape of NSCLC by binding to HuR and increasing PD-L1 and USP8 levels.
Keywords Non-small cell lung cancer, LncRNA SNHG12, PD-L1, USP8, Immune escape, HuR, Peripheral blood mononuclear cells, CD8+ T
Address and Contact Information 1 Department of Cancer Center, The Second Afliated Hospital of Chongqing Medical University, Tianwen Avenue No. 288, Nan’an District, Chongqing 400010, China
2 Chongqing University, Three Gorges Hospital, No. 165 Xincheng Road, Wanzhou District, Chongqing 404100, China
*Correspondence: lixizi19620716@163.com; yangzhenzhou@sohu.com
Yusheng Huang, Lei Xia, and Xiangwu Tan contributed equally to this work.
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No.  44DOI: 10.1186/s11658-022-00345-5 Volume 27 (2022) - 27:44
Authors Shengyu Hao1†, Fan Li2†, Pan Jiang2* and Jian Gao2*
Abstract Background: Obstructive sleep apnea is associated with increased lung cancer incidence and mortality. Cancer stem cells (CSCs) are characterized by their self-renewing ability, which contributes to metastasis, recurrence, and drug resistance. ATPase family AAA domain-containing protein 2 (ATAD2) induces malignancy in diferent types of tumors. However, a correlation between ATAD2 expression and CSCs in lung cancer has not yet been reported.
Methods: The relative messenger RNA (mRNA) levels of ATAD2, CD44, CD133, and hypoxia-inducible factor (HIF)-1α were determined using reverse-transcription quantitative polymerase chain reaction. ATAD2 protein levels were determined using Western blotting. Cell counting kit-8, 5-ethynyl-2′-deoxyuridine (EdU), and colony formation assays were performed to analyze the proliferation of lung cancer cells. Transwell migration and invasion assays were performed to evaluate cell migration and invasion, respectively. Tumor sphere formation analysis was used to determine tumor spheroid capacity. The link between ATAD2 and HIF-1α was verifed using a dual-luciferase reporter assay. Immunofuorescence staining was performed to assess mitochondrial reactive oxygen species (mtROS) production. Flow cytometry analysis was conducted to determine the CD133 and CD44 positive cell ratio.
Results: We evaluated the relative expression of ATAD2 in four lung cancer cell lines (A549, SPC-A1, H460, and H1299 cells) and found increased mRNA and protein levels of ATAD2 in lung cancer samples. ATAD2 overexpression was a poor prognostic factor for lung cancer patients. Loss of ATAD2 reduced lung cancer cell viability and proliferation. Additionally, ATAD2 knockdown repressed lung cancer cell migration, invasion, stem-cell-like properties, and mtROS production. Chronic intermittent hypoxia (CIH)-induced HIF-1α expression signifcantly activated ATAD2 during lung cancer progression.
Conclusions: This study found that CIH induced HIF-1α expression, which acts as a transcriptional activator of ATAD2. The present study also suggests a novel mechanism by which the integrity of CIH-triggered HIF-1α/ATAD2 may determine lung cancer aggressiveness via the interplay of mtROS and stemness in lung cancer cells.
Keywords ATAD2, Lung cancer stem cells, CIH, HIF-1α
Address and Contact Information 1 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2 Department of Nutrition, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
*Correspondence: jiang.pan@zs-hospital.sh.cn; gao.jian@zs-hospital.sh.cn
Shengyu Hao and Fan Li contributed equally to this work.
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No.  45DOI: 10.1186/s11658-022-00351-7 Volume 27 (2022) - 27:45
Authors Anna Muchlińska1, Anna Nagel1, Marta Popęda1, Jolanta Szade2, Magdalena Niemira3, Jacek Zieliński4, Jarosław Skokowski4,5, Natalia Bednarz‐Knoll1 and Anna J. Żaczek1*
Abstract Background: Cancer-associated fbroblasts (CAFs) have been shown to support tumor development in a variety of cancers. Diferent markers were applied to classify CAFs in order to elucidate their impact on tumor progression. However, the exact mechanism by which CAFs enhance cancer development and metastasis is yet unknown.
Methods: Alpha-smooth muscle actin (α-SMA) was examined immunohistochemically in intratumoral CAFs of nonmetastatic breast cancers and correlated with clinico‐pathological data. Four CAF cell lines were isolated from patients with luminal breast cancer (lumBC) and classifed according to the presence of α-SMA protein. Conditioned medium (CM) from CAF cultures was used to assess the infuence of CAFs on lumBC cell lines: MCF7 and T47D cells using Matrigel 3D culture assay. To identify potential factors accounting for promotion of tumor growth by α-SMAhigh CAFs, nCounter PanCancer Immune Profling Panel (NanoString) was used.
Results: In luminal breast cancer, presence of intratumoral CAFs expressing high level of α-SMA (13% of lumBC group) correlated with poor prognosis (p=0.019). In in vitro conditions, conditioned medium obtained from primary cultures of α-SMA-positive CAFs isolated from luminal tumors was observed to enhance growth of lumBC cell line colonies in 3D Matrigel, in contrast to CM derived from α-SMA-negative CAFs. Multigene expression analysis indicated that osteopontin (OPN) was overexpressed in α-SMA-positive CAFs in both clinical samples and in vitro models. OPN expression was associated with higher percentage of Ki67-positive cells in clinical material (p=0.012), while OPN blocking in α-SMA-positive CAF-derived CM attenuated growth of lumBC cell line colonies in 3D Matrigel.
Conclusions: Our fndings demonstrate that α-SMA-positive CAFs might enhance tumor growth via secretion of OPN.
Keywords Cancer-associated fbroblast, Luminal breast cancer, Alpha-smooth muscle actin, Osteopontin
Address and Contact Information 1 Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80‐211 Gdansk, Poland
2 Department of Pathomorphology, Medical University of Gdansk, 80‐214 Gdansk, Poland
3 Clinical Research Centre, Medical University of Bialystok, 15‐276 Bialystok, Poland
4 Department of Surgical Oncology, Medical University of Gdansk, 80‐214 Gdansk, Poland
5 Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.PL), 80‐211 Gdansk, Poland
*Correspondence: azaczek@gumed.edu.pl
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No.  46DOI: 10.1186/s11658-022-00333-9 Volume 27 (2022) - 27:46
Authors Wenping Luo1,2†, Panpan Liang1,3†, Tianyu Zhao3,4, Qianyu Cheng3, Huikai Liu3, Liwen He1,2, Linghuan Zhang5, Bo Huang6, Yuxin Zhang3, Tongchuan He2 and Deqin Yang1,3*
Abstract The submandibular gland (SMG) and the sublingual gland (SLG) are two of the three major salivary glands in mammals. In mice, they are adjacent to each other and open into the oral cavity, producing saliva to lubricate the mouth and aid in food digestion. Though salivary gland dysfunction accompanied with fbrosis and metabolic disturbance is common in clinic, in-depth mechanistic research is lacking. Currently, research on how to rescue salivary function is challenging, as it must resort to using terminally diferentiated acinar cells or precursor acinar cells with unknown diferentiation. In this study, we established reversely immortalized mouse primary SMG cells (iSMGCs) and SLG cells (iSLGCs) on the frst postnatal day (P0). The iSMGCs and iSLGCs grew well, exhibited many salivary gland characteristics, and retained the metabolism-related genes derived from the original tissue as demonstrated using transcriptome sequencing (RNA-seq) analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of these two cell lines, which overlapped with those of the SMG and SLG, were enriched in cysteine and methionine metabolism. Furthermore, we investigated the role of bone morphogenetic protein 9 (BMP9), also known as growth diferentiation factor 2(Gdf2), on metabolic and fbrotic functions in the SMG and SLG. We demonstrated that iSMGCs and iSLGCs presented promising adipogenic and fbrotic responses upon BMP9/Gdf2 stimulation. Thus, our fndings indicate that iSMGCs and iSLGCs faithfully reproduce characteristics of SMG and SLG cells and present a promising prospect for use in future study of salivary gland metabolism and fbrosis upon BMP9/Gdf2 stimulation.
Keywords Submandibular gland, Sublingual gland, Immortalization, Metabolism, Fibrosis, BMP9/Gdf2
Address and Contact Information 1 Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, 426 Songshi North Road, Yubei District, Chongqing 401147, China.
2 Department of Surgery, Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, The University of Chicago Medical Center, 5841 South Maryland Avenue MC6035, Chicago, IL 60637, USA.
3 Stomatological Hospital of Chongqing Medical University, 426 Songshi North Road, Yubei District, Chongqing 401147, China.
4 Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, 426 Songshi North Road, Yubei District, Chongqing 401147, China.
5 Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children’s Hospital of Chongqing Medical University, Chongqing 400014, China.
6 Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Afliated Hospital of Nanchang University, No.1 Min De Road, Nanchang 330006, China.
*Corresponding author: yangdeqin@hospital.cqmu.edu.cn
Wenping Luo and Panpan Liang equally contributed to this work.
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No.  47DOI: 10.1186/s11658-022-00346-4 Volume 27 (2022) - 27:47
Authors Jian‐Zhi Zhao1,2†, Qi‐Yao Li3†, Jia‐Jie Lin1†, Li‐Yun Yang1, Mei‐Yang Du1, Yu Wang1, Ke‐Xin Liu1, Ze‐An Jiang1, Huan‐Huan Li1, Si‐Fan Wang1, Bo Sun1, Shi‐Qing Mu1, Bin Li1, Kun Liu1, Miao Gong1 and Shao‐Guang Sun1*
Abstract Background: Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling diseases. Recently, it has been discovered that tRNA-derived small RNAs (tsRNAs), a new type of noncoding RNAs, are related to the proliferation and migration of VSMCs. tsRNAs regulate target gene expression through miRNA-like functions. This study aims to explore the potential of tsRNAs in human aortic smooth muscle cell (HASMC) proliferation.
Methods: High-throughput sequencing was performed to analyze the tsRNA expression profle of proliferative and quiescent HASMCs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the sequence results and subcellular distribution of AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076. Based on the microRNA-like functions of tsRNAs, we predicted target promoters and mRNAs and constructed tsRNA–promoter and tsRNA–mRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the function of target genes. EdU incorporation assay, Western blot, and dual-luciferase reporter gene assay were utilized to detect the efects of tsRNAs on HASMC proliferation.
Results: Compared with quiescent HASMCs, there were 1838 diferentially expressed tsRNAs in proliferative HASMCs, including 887 with increased expression (fold change>2, p<0.05) and 951 with decreased expression (fold change<1⁄2, p<0.05). AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076 were increased in proliferative HASMCs and were mainly located in the nucleus. Bioinformatics analysis suggested that the four tsRNAs involved a variety of GO terms and pathways related to VSMC proliferation. AS-tDR-000067 promoted HASMC proliferation by suppressing p53 transcription in a promoter-targeted manner. AS-tDR-000076 accelerated HASMC proliferation by attenuating mitofusin 2 (MFN2) levels in a 3′-untranslated region (UTR)-targeted manner.
Conclusions: During HASMC proliferation, the expression levels of many tsRNAs are altered. AS-tDR-000067 and AS-tDR-000076 act as new factors promoting VSMC proliferation.
Keywords tsRNA, VSMC, proliferation, p53, MFN2
Address and Contact Information 1 Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, China
2 Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
3Department of Emergency Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
*Corresponding author: sunshaoguang00@163.com
Jian-Zhi Zhao, Qi-Yao Li, and Jia-Jie Lin contributed equally to this work.
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No.  48DOI: 10.1186/s11658-022-00353-5 Volume 27 (2022) - 27:48
Authors Dong Suwei1,2†, Xiao Yanbin2,4*†, Wang Jianqiang1†, Ma Xiang2, Peng Zhuohui2, Kang Jianping2, Wang Yunqing1,4* and Li Zhen3,4*
Abstract Melanoma is the most lethal skin cancer characterized by its high metastatic potential. It is urgent to fnd novel therapy strategies to overcome this feature. Metformin has been confrmed to suppress invasion and migration of various types of cancer. However, additional mechanisms underlying the antimetastatic efect of metformin on melanoma require further investigation. Here, we performed microarray analysis and uncovered an altered mRNA and miRNA expression profle between melanoma and nevus. Luciferase reporter assay confrmed that miR-5100 targets SPINK5 to activate STAT3 phosphorylation. Migration and wound healing assays showed that the miR-5100/SPINK5/STAT3 axis promotes melanoma cell metastasis; the mechanism was proven by initiation of epithelial–mesenchymal transition. Co-immunoprecipitation (Co-IP) further confrmed an indirect interaction between SPINK5 and STAT3. Furthermore, metformin dramatically inhibited miR-5100/SPINK5/STAT3 pathway, and decreased B16-F10 cell metastasis to lung in C57 mouse module. Intriguingly, pretreatment of metformin before melanoma cell injection improved this efect further. These fndings exposed the underlying mechanisms of action of metformin and update the use of this drug to prevent metastasis in melanoma.
Keywords EMT, miR-5100, Metformin, SPINK5, STAT3
Address and Contact Information 1 Department of Orthopaedics, The Second Afliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China
2 Department of Orthopaedics, The Third Afliated Hospital of Kunming Medical University, Kunming 650118, People’s Republic of China
3 Department of Medical Oncology, The Second Afliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China
4 The Second Afliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China
*Corresponding author: xiaoyanbin73@126.com; kzwangyunqing@163.com; lizhenres@163.com
Dong Suwei, Xiao Yanbin and Wang Jianqiang contribute equally to this work
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No.  49DOI: 10.1186/s11658-022-00348-2 Volume 27 (2022) - 27:49
Authors Mostafa Vaghari‐Tabari1, Parisa Hassanpour1, Fatemeh Sadeghsoltani1, Faezeh Malakoti1, Forough Alemi1, Durdi Qujeq2,3, Zatollah Asemi4* and Bahman Yousef1,5*
Abstract The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efcient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the efectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of diferent cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the efectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.
Keywords CRISPR/Cas9, Gene editing, Chemoresistance, Malignancy, Cancer treatment
Address and Contact Information 1 Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
2 Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran
3 Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
4 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
5 Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
*Correspondence: asemi_r@yahoo.com; yousefb@tbzmed.ac.ir
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No.  50DOI: 10.1186/s11658-022-00352-6 Volume 27 (2022) - 27:50
Authors Mohammadreza Saberiyan1, Elham Karimi2, Zahra Khademi3, Parvaneh Movahhed4, Amir Saf5 and Ameneh Mehri‐Ghahfarrokhi6*
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of corona‐virus disease 2019 (COVID-19), a major international public health concern. Because of very similar amino acid sequences of the seven domain names, SARS-CoV-2 belongs to the Coronavirinae subfamily of the family Coronaviridae, order Nidovirales, and realm Riboviria, placed in exceptional clusters, but categorized as a SARS-like species. As the RNA virus family with the longest genome, the Coronaviridae genome consists of a single strand of positive RNA (25–32 kb in length). Four major structural proteins of this genome include the spike (S), membrane (M), envelope (E), and the nucleocapsid (N) protein, all of which are encoded within the 3′ end of the genome. By engaging with its receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 infects host cells. According to the most recent epidemiological data, as the illness spread globally, several genetic variations of SARS-CoV-2 appeared quickly, with the World Health Organization (WHO) naming 11 of them. Among these, seven SARS-CoV-2 subtypes have received the most attention. Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.617.2) are now designated as variations of concern (VOC) (B.1.1.529). Lambda (C.37) and Mu are variations of interest (VOI) (B.1.621). The remaining six are either being monitored or are no longer considered a threat. On the basis of studies done so far, antiviral drugs, antibiotics, glucocorticoids, recombinant intravenous immunoglobulin, plasma therapy, and IFN-α2b have been used to treat patients. Moreover, full vaccination is associated with lower infection and helps prevent transmission, but the risk of infection cannot be eliminated completely in vaccinated people.
Keywords SARS-CoV-2 variants, Omicron, COVID-19, Vaccine
Address and Contact Information 1 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
2 Department of Medical Genetics, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
3 Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
4 Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
5 Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
6 Clinical Research Development Unit, Hajar Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran
*Corresponding author: ameneh.mehri.96@gmail.com
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No.  51DOI: 10.1186/s11658-022-00350-8 Volume 27 (2022) - 27:51
Authors Jianzi Lan*, Bowen Xu, Xin Shi, Qi Pan and Qing Tao
Abstract Background: Diabetic nephropathy (DN) is prevalent in patients with diabetes. N6-methyladenosine (m6A) methylation has been found to cause modifcation of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3, which is involved in cell pyroptosis and infammation. WTAP is a key gene in modulating NLRP3 m6A.
Methods: In this study, WTAP was silenced or overexpressed in high glucose (HG)-treated HK-2 cells to determine its infuence on pyroptosis, NLRP3 infammasome-related proteins, and the release of pro-infammatory cytokines. NLRP3 expression and m6A levels were assessed in the presence of WTAP shRNA (shWTAP). WTAP expression in HK-2 cells was examined with the introduction of C646, a histone acetyltransferase p300 inhibitor.
Results: We found that WTAP expression was enhanced in patients with DN and in HG-treated HK-2 cells. Knockdown of WTAP attenuated HG-induced cell pyroptosis and NLRP3-related pro-infammatory cytokines in both HK-2 cells and db/db mice, whereas WTAP overexpression promoted these cellular processes in HK-2 cells. WTAP mediated the m6A of NLRP3 mRNA that was stabilized by insulin-like growth factor 2 mRNA binding protein 1. Histone acetyltransferase p300 regulated WTAP expression. WTAP mRNA levels were positively correlated with NLRP3 infammasome components and pro-infammatory cytokines.
Conclusion: Taken together, WTAP promotes the m6A methylation of NLRP3 mRNA to upregulate NLRP3 infammasome activation, which further induces cell pyroptosis and infammation.
Keywords WTAP, NLRP3, Pyroptosis, High glucose, N6-methyladenosine, Infammation
Address and Contact Information Department of Traditional Chinese Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150, Jimo Road, Pudong District, Shanghai 200120, China
*Correspondence: dfsl112@126.com
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No.  52DOI:10.1186/s11658-022-00344-6 Volume 27 (2022) - 27:52
Authors Mohsen Karami Fath1, Ali Azargoonjahromi2, Arash Kiani3, Fateme Jalalifar4, Parisa Osati5, Mahsa Akbari Oryani6, Fateh Shakeri1, Farhad Nasirzadeh1, Behman Khalesi7, Mohsen Nabi‐Aadi8, Hamidreza Zalpoor9,10, Maysam Mard‐Soltani11* and Zahra Payandeh12*
Abstract Background: Breast cancer is defined as a biological and molecular heterogeneous disorder that originates from breast cells. Genetic predisposition is the most important factor giving rise to this malignancy. The most notable mutations in breast cancer occur in the BRCA1 and BRCA2 genes. Owing to disease heterogeneity, lack of therapeutic target, anti-cancer drug resistance, residual disease, and recurrence, researchers are faced with challenges in developing strategies to treat patients with breast cancer.
Results: It has recently been reported that epigenetic processes such as DNA methylation and histone modification, as well as microRNAs (miRNAs), have potently contributed to the pathophysiology, diagnosis, and treatment of breast cancer. These observa‐tions have persuaded researchers to move their therapeutic approaches beyond the genetic framework toward the epigenetic concept.
Conclusion: Herein we discuss the molecular and epigenetic mechanisms underlying breast cancer progression and resistance as well as various aspects of epigenetic-based therapies as monotherapy and combined with immunotherapy.
Keywords Breast cancer, Epigenetic modifications, microRNAs, Treatment, Chemoresistance
Address and Contact Information 1 Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
2 Shiraz University of Medical Sciences, Shiraz, Iran.
3 Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran.
4 School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran.
5 Chemical Engineering Department, Fouman Faculty of Engineering, College of Engineering, University of Tehran, Fouman, Iran.
6 Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
7 Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Karaj, Iran.
8 Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
9 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
10 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
11 Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
12 Department Medical Biochemistry and Biophysics, Division Medical Infammation Research, Karolinska Institute, Stockholm, Sweden.
*Corresponding author: maysam.mardsoltani@gmail.com; Zpayandeh58@yahoo.com
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No.  53DOI: 10.1186/s11658-022-00347-3 Volume 27 (2022) - 27:53
Authors Kate Tubbesing1,2,3,6, Nicholas Moskwa2,3,5, Ting Chean Khoo1, Deirdre A. Nelson2,3, Anna Sharikova1, Yunlong Feng4, Melinda Larsen2,3* and Alexander Khmaladze1*
Abstract Background: Organoids, which are organs grown in a dish from stem or progenitor cells, model the structure and function of organs and can be used to defne molecular events during organ formation, model human disease, assess drug responses, and perform grafting in vivo for regenerative medicine approaches. For therapeutic applications, there is a need for nondestructive methods to identify the diferentiation state of unlabeled organoids in response to treatment with growth factors or pharmacologicals.
Methods: Using complex 3D submandibular salivary gland organoids developed from embryonic progenitor cells, which respond to EGF by proliferating and FGF2 by undergoing branching morphogenesis and proacinar diferentiation, we developed Raman confocal microspectroscopy methods to defne Raman signatures for each of these organoid states using both fxed and live organoids.
Results: Three separate quantitative comparisons, Raman spectral features, multivariate analysis, and machine learning, classifed distinct organoid diferentiation signatures and revealed that the Raman spectral signatures were predictive of organoid phenotype. Conclusions: As the organoids were unlabeled, intact, and hydrated at the time of imaging, Raman spectral fngerprints can be used to noninvasively distinguish between diferent organoid phenotypes for future applications in disease modeling, drug screening, and regenerative medicine.
Keywords Raman spectroscopy, Tissue-engineered organoids, Salivary gland organoids, Regenerative medicine
Address and Contact Information 1 Department of Physics, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
2 Department of Biological Sciences, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
3 RNA Institute, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
4 Department of Mathematics, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
5 Present Address: The Jackson Laboratory, 10 Discovery Dr., Farmington, CT 06032, USA
6 Present Address: Neural Stem Cell Institute, Rensselaer, NY 12144, USA
*Corresponding author: mlarsen@albany.edu; akhmaladze@albany.edu
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No.  54DOI: 10.1186/s11658-022-00357-1 Volume 27 (2022) - 27:54
Authors María Victoria Castro1,2, Gastón Alexis Barbero1,2, Paula Máscolo1, Rocío Ramos1, María Josefna Quezada1,2 and Pablo Lopez‐Bergami1,2*
Abstract Correction to: Cellular & Molecular Biology Letters (2022) 27:23

Following publication of the original article [1], the authors identifed a few errors in panel A of Fig. 4. Two western blot images from panel B (Bcl-xL and Actin) were duplicated by mistake into panel A in place of the western blots for MDM2 and the Actin controls for both MDM2 and p53. Te correct Fig. 4 is given in this correction article.
Keywords ROR2, ERK, Melanoma, Chemoresistance, Apoptosis
Address and Contact Information 1 Centro de Estudios Biomédicos, Básicos, Biotecnológicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Hidalgo 775, 6th Floor, Lab 602, 1405 Buenos Aires, Argentina
2 Consejo Nacional de Investigaciones Científcas y TécniCas (CONICET), 1425 Buenos Aires, Argentina
*Corresponding author: lopezbergami.pablo@maimonides.edu
The original article can be found online at https://doi.org/10.1186/s11658-​022-​00327-7
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