Vol. 26 (2021)

No. 1DOI: 10.1186/s11658-020-00245-6 Volume 26 (2021) - 26:1
Authors Michal Tracz and Wojciech Bialek*
Abstract Protein ubiquitination has become one of the most extensively studied post-translational modifications. Originally discovered as a critical element in highly regulated proteolysis, ubiquitination is now regarded as essential for many other cellular processes. This results from the unique features of ubiquitin (Ub) and its ability to form various homo- and heterotypic linkage types involving one of the seven different lysine residues or the free amino group located at its N-terminus. While K48- and K63-linked chains are broadly covered in the literature, the other types of chains assembled through K6, K11, K27, K29, and K33 residues deserve equal attention in the light of the latest discoveries. Here, we provide a concise summary of recent advances in the field of these poorly understood Ub linkages and their possible roles in vivo.
Keywords Ubiquitin, Non-canonical, Atypical ubiquitination, Ubiquitin chains
Address and Contact Information Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
*Corresponding author: wojciech.bialek@uwr.edu.pl
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No. 2 DOI: 10.1186/s11658-020-00244-7 Volume 26 (2021) - 26:2
Authors Shujuan Zhou1†, Lan Sun1†, Shanhu Qian1, Yongyong Ma1, Ruye Ma1, Yuqing Dong1, Yifen Shi1, Songfu Jiang1, Haige Ye1, Zhijian Shen1, Shenghui Zhang1, Jianping Shen2*, Kang Yu1* and Siqian Wang3*
Abstract Background: Iron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism.
Methods: We established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload.
Results: Iron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy.
Conclusions: Our results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.
Keywords Curcumin, Iron overload, Bone marrow damage, Autophagy, Mitochondrial ROS
Address and Contact Information 1 Department of Haematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China
2 Department of Haematology, The First Affiliated Hospital of Zhejiang Chinese Medical University; The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People’s Republic of China
3 Department of Prosthodontics, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China
*Corresponding author: shengjianping@163.com; 20442947@qq.com; wsq982004@163.com
Shujuan Zhou and Lan Sun contributed equally to this work
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No. 3 DOI: 10.1186/s11658-020-00246-5 Volume 26 (2021) - 26:3
Authors Wenqing Liang1*†, Xiaozhen Chen2†, Songou Zhang2†, Jian Fang2, Meikai Chen3, Yifan Xu3 and Xuerong Chen3
Abstract Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial–mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites
Keywords Angiogenesis, Cancer-associated fibroblasts, Immunosuppression, Metastasis, Mesenchymal stem cells
Address and Contact Information 1 Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang, People’s Republic of China
2 College of Medicine, Shaoxing University, Shaoxing 312000, Zhejiang, People’s Republic of China.
3 Department of Orthopaedics, Shaoxing People’s Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang, People’s Republic of China
*Corresponding author: drliangwenqing@yeah.net
Wenqing Liang, Xiaozhen Chen and Songou Zhang contributed equally to this work
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No. 4 DOI: 10.1186/s11658-021-00248-x Volume 26 (2021) - 26:4
Authors Emmanuel Odame, Yuan Chen, Shuailong Zheng, Dinghui Dai, Bismark Kyei, Siyuan Zhan, Jiaxue Cao, Jiazhong Guo, Tao Zhong, Linjie Wang, Li Li* and Hongping Zhang*
Abstract miRNAs are well known to be gene repressors. A newly identified class of miRNAs termed nuclear activating miRNAs (NamiRNAs), transcribed from miRNA loci that exhibit enhancer features, promote gene expression via binding to the promoter and enhancer marker regions of the target genes. Meanwhile, activated enhancers produce endogenous non-coding RNAs (named enhancer RNAs, eRNAs) to activate gene expression. During chromatin looping, transcribed eRNAs interact with NamiRNAs through enhancer-promoter interaction to perform similar functions. Here, we review the functional differences and similarities between eRNAs and NamiRNAs in myogenesis and disease. We also propose models demonstrating their mutual mechanism and function. We conclude that eRNAs are active molecules, transcriptional regulators, and partners of NamiRNAs, rather than mere RNAs produced during enhancer activation.
Keywords Enhancer RNA, NamiRNAs, MicroRNA, Myogenesis, Transcriptional regulator
Address and Contact Information Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
*Corresponding author: lily@sicau.edu.cn; zhp@sicau.edu.cn
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No. 5 DOI: 10.1186/s11658-020-00243-8 Volume 26 (2021) - 26:5
Authors Emilia Lekholm1,2*, Mikaela M. Ceder2, Erica C. Forsberg2, Helgi B. Schiöth1,3 and Robert Fredriksson2
Abstract Background: The synaptic vesicle glycoprotein 2 (SV2) family is essential to the synaptic machinery involved in neurotransmission and vesicle recycling. The isoforms SV2A, SV2B and SV2C are implicated in neurological diseases such as epilepsy, Alzheimer’s and Parkinson’s disease. Suitable cell systems for studying regulation of these proteins are essential. Here we present gene expression data of SV2A, SV2B and SV2C in two human neuroblastoma cell lines after differentiation.
Methods: Human neuroblastoma cell lines SiMa and IMR-32 were treated for seven days with growth supplements (B-27 and N-2), all-trans-retinoic acid (ATRA) or vasoactive intestinal peptide (VIP) and gene expression levels of SV2 and neuronal targets were analyzed.
Results: The two cell lines reacted differently to the treatments, and only one of the three SV2 isoforms was affected at a time. SV2B and choline O-acetyltransferase (CHAT) expression was changed in concert after growth supplement treatment, decreasing in SiMa cells while increasing in IMR-32. ATRA treatment resulted in no detected changes in SV2 expression in either cell line while VIP increased both SV2C and dopamine transporter (DAT) in IMR-32 cells.
Conclusion: The synergistic expression patterns between SV2B and CHAT as well as between SV2C and DAT mirror the connectivity between these targets found in disease models and knock-out animals, although here no genetic alteration was made. These cell lines and differentiation treatments could possibly be used to study SV2 regulation and function.
Keywords Neuroblastoma, Differentiation, SV2A, SV2B, SV2C, Synaptic vesicle protein
Address and Contact Information 1 Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
2 Molecular Neuropharmacology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
3 Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia
*Corresponding author: Emilia.Lekholm@farmbio.uu.se
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No. 6 DOI: 10.1186/s11658-021-00247-y Volume 26 (2021) - 26:6
Authors Yu Liu1, Risheng Huang2*, Deyao Xie1, Xiaoming Lin1 and Liangcheng Zheng1
Abstract Background: ZNF674-AS1, a recently characterized long noncoding RNA, shows prognostic significance in hepatocellular carcinoma and glioma. However, the expression and function of ZNF674-AS1 in non-small cell lung cancer (NSCLC) are unclear.
Methods: In this work, we investigated the expression of ZNF674-AS1 in 83 pairs of NSCLC specimens and adjacent noncancerous lung tissues. The clinical significance of ZNF674-AS1 in NSCLC was analyzed. The role of ZNF674-AS1 in NSCLC growth and cell cycle progression was explored.
Results: Our data show that ZNF674-AS1 expression is decreased in NSCLC compared to normal tissues. ZNF674-AS1 downregulation is significantly correlated with advanced TNM stage and decreased overall survival of NSCLC patients. Overexpression of ZNF674-AS1 inhibits NSCLC cell proliferation, colony formation, and tumorigenesis, which is accompanied by a G0/G1 cell cycle arrest. Conversely, knockdown of ZNF674-AS1 enhances the proliferation and colony formation of NSCLC cells. Biochemically, ZNF674-AS1 overexpression increases the expression of p21 through downregulation of miR-423-3p. Knockdown of p21 or overexpression of miR-423-3p blocks ZNF674-AS1-mediated growth suppression and G0/G1 cell cycle arrest. In addition, ZNF674-AS1 expression is negatively correlated with miR-423-3p in NSCLC specimens.
Conclusions: ZNF674-AS1 suppresses NSCLC growth by downregulating miR-423-3p and inducing p21. This work suggests the therapeutic potential of ZNF674-AS1 in the treatment of NSCLC.
Keywords Cell cycle arrest, Cell growth, p21, ZNF674-AS1
Address and Contact Information 1 Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
2 Department of Thoracic Surgery, Wenzhou Central Hospital, Wenzhou, China
*Corresponding author: hrs9900@163.com
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No. 7 DOI: 10.1186/s11658-021-00249-w Volume 26 (2021) - 26:7
Authors Chong Zeng1*, Zhongbao Shao2, Zibo Wei1, Jie Yao1, Weidong Wang3, Liang Yin4, Huixian YangOu5 and Dan Xiong6*
Abstract Background: NOTCH signaling has been shown to play a role in the production of interleukin-22 (IL-22) by CD4+ T cells. Multiple T-helper (Th) cell populations secrete IL-22. Th22 (CD4+IL22+IFNγIL17A ) cells are a subgroup of CD4+ effector T cells that primarily generate IL-22. The regulatory mechanisms of the NOTCH signaling pathway involved in differentiation of the Th22 cell subset have not been completely elucidated. This study aimed to further explore the involvement of NOTCH signaling in Th22 differentiation.
Methods: In vitro combination of IL-6, IL-23, and tumor necrosis factor-α (TNF-α) treatment with naïve CD4+ T cells established the Th22 cell induced model. NOTCH signaling was activated by jagged-1 and inhibited by (2S)-N-[(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl]glycine 1,1-dimethylethyl ester (DAPT). HES-1 siRNA and HES-1 vector were employed to knock down and induce overexpression of HES-1 to investigate the effect of NOTCH signaling on the differentiation of CD4+ T cells into Th22 cells.
Results: We observed that the proportion of Th22 cells, along with Hes-1, Ahr, and Il-22 mRNA and protein expression, was increased by both jagged-1 and overexpression of HES-1. On the other hand, after the combined cytokine treatment of cells, and exposure to jagged-1 and DAPT or HES-1 siRNA, there was a decrease in the Th22 cell proportion, mRNA and protein expression of HES-1, AHR, and IL-22.
Conclusions: Our study demonstrates that HES-1 enhancement in AHR and IL-22 upregulation of NOTCH signaling can promote the skewing of naïve CD4+ T cells toward Th22 cells. Also, the results of our study show that HES-1 is a crucial factor in Th22 cell differentiation.
Keywords CD4 + T cells, NOTCH signaling, HES-1, Th22, Differentiation
Address and Contact Information 1 Medical Research Center, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528300, China
2 Department of Electronic Information Engineering, Guangzhou College of Technology and Business, Foshan, China.
3 Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528300, China.
4 Department of Endocrinology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528300, China.
5 Department of Anesthesiology Operating Room, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528300, China.
6 Department of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong, China
*Corresponding author: wonder10@126.com; xiongdancn@aliyun.com
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No. 8 DOI: 10.1186/s11658-021-00252-1 Volume 26 (2021) - 26:8
Authors Yan Hao, Haitao Yuan* and Houzhi Yu*
Abstract Retraction to: Hao et al. Cellular & Molecular Biology Letters (2020) 25:20 https ://doi.org/10.1186/s11658-020-00213-0
The authors have retracted this article because they found that some of the published data related to Fig. 5c were biased or even reversed in subsequent repeated experiments. All authors agree to this retraction.

The original article can be found online at https ://doi.org/10.1186/s11658-020-00213-0.
Address and Contact Information Department of Cardiology, Shandong Provincial Hospital Affiliated To Shandong University, 324 Jingwu Road, Jinan 250021, Shandong, China
*Corresponding author: yuan_haitao0204@126.com; yeuosjdliyuaj23@2980.comS
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No. 9 DOI: 10.1186/s11658-021-00251-2 Volume 26 (2021) - 26:9
Authors Hao Chen1†, Min Luo2†, Xiangping Wang2, Ting Liang2, Chaoyuan Huang2, Changjie Huang2* and Lining Wei2*
Abstract Background: Nasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity.
Methods: We enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done.
Results: Our data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation.
Conclusions: PAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.
Keywords PAD4, GSK484, Radiosensitivity, Nasopharyngeal carcinoma
Address and Contact Information 1 Department of Endoscopy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
2 Department of Oncology, The Second Nanning People’s Hospital, No.13 Dancun Road, Jiangnan District, Nanning 530031, Guangxi, China
* Corresponding Author: hcj1215423068@hotmail.com; weilininggudy@163.com
Hao Chen and Min Luo contributed equally to this work
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No. 10 DOI: 10.1186/s11658-021-00253-0 Volume 26 (2021) - 26:10
Authors Marcin Woźniak1,2, Christian J. Konopka2,3, Agata Płoska1,4, Jamila Hedhli2, Anna Siekierzycka1, Maciej Banach7, Rafal Bartoszewski8, Lawrence W. Dobrucki1,2,3,4,5,6, Leszek Kalinowski1,4,9* and Iwona T. Dobrucki2,3*
Abstract Background: Molecular imaging with molecularly targeted probes is a powerful tool for studying the spatio-temporal interactions between complex biological processes. The pivotal role of the receptor for advanced glycation end products (RAGE), and its involvement in numerous pathological processes, aroused the demand for RAGE-targeted imaging in various diseases. In the present study, we evaluated the use of a diagnostic imaging agent for RAGE quantification in an animal model of peripheral artery disease, a multimodal dual-labeled probe targeted at RAGE (MMIA-CML).
Methods: PAMAM dendrimer was conjugated with Nε-carboxymethyl-lysine (CML) modified albumin to synthesize the RAGE-targeted probe. A control untargeted agent carried native non-modified human albumin (HSA). Bifunctional p-SCN-Bn-NOTA was used to conjugate the 64Cu radioisotope. Surgical right femoral artery ligation was performed on C57BL/6 male mice. One week after femoral artery ligation, mice were injected with MMIA-CML or MMIA-HSA labeled with 64Cu radioisotope and 60 min later in vivo microPET-CT imaging was performed. Immediately after PET imaging studies, the murine hindlimb muscle tissues were excised and prepared for gene and protein expression analysis. RAGE gene and protein expression was assessed using real-time qPCR and Western blot technique respectively. To visualize RAGE expression in excised tissues, microscopic fluorescence imaging was performed using RAGE-specific antibodies and RAGE-targeted and -control MMIA.
Results: Animals subjected to PET imaging exhibited greater MMIA-CML uptake in ischemic hindlimbs than non-ischemic hindlimbs. We observed a high correlation between fluorescent signal detection and radioactivity measurement. Significant RAGE gene and protein overexpression were observed in ischemic hindlimbs compared to non-ischemic hindlimbs at one week after surgical ligation. Fluorescence microscopic staining revealed significantly increased uptake of RAGE-targeted nanoparticles in both ischemic and non-ischemic muscle tissues compared to the control probe but at a higher level in ischemic hindlimbs. Ischemic tissue exhibited explicit RAGE dyeing following anti-RAGE antibody and high colocalization with the MMIA-CML targeted at RAGE.
Conclusions: The present results indicate increased expression of RAGE in the ischemic hindlimb and enable the use of multimodal nanoparticles in both in vitro and in vivo experimental models, creating the possibility for imaging structural and functional changes with a RAGE-targeted tracer.
Keywords RAGE, AGEs, Molecular imaging, Ischemia
Address and Contact Information 1 Department of Medical Laboratory Diagnostics – Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 7 Debinki Street, 80–211, Gdansk, Poland.
2 University of Illinois at Urbana-Champaign Beckman Institute for Advanced Science and Technology, 405 N Mathews Ave, MC-251, 61801 Urbana, IL, USA.
3 Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
4 Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.pl), Gdansk, Poland.
5 Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
6 Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
7 Department of Hypertension, Medical University of Lodz, Lodz, Poland.
8 Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
9 BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, Gdansk, Poland.
*Corresponding author: leszek.kalinowski@gumed.edu.pl; dobrucka@illinois.edu
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No. 11 DOI: 10.1186/s11658-021-00255-y Volume 26 (2021) - 26:11
Authors Sylwia Bartoszewska1*, Jarosław Króliczewski2, David K. Crossman3, Aneta Pogorzelska4, Maciej Bagiński5, James F. Collawn6 and Rafal Bartoszewski2*
Abstract Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.
Keywords XBP1s, UPR, ER stress, IRE1α
Address and Contact Information 1 Department of Inorganic Chemistry, Medical University of Gdansk, Hallera 107, 80-416 Gdańsk, Poland.
2 Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Hallera 107, 80-416 Gdańsk, Poland.
3 Department of Genetics, Heflin Center for Genomic Science, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
4 Department of Organic Chemistry, Medical University of Gdansk, Gdansk, Poland.
5 Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, 80-233 Gdańsk, Poland.
6 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
*Corresponding author: sylwiabart@gumed.edu.pl; rafalbar@gumed.edu.pl
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No. 12 DOI: 10.1186/s11658-021-00256-x Volume 26 (2021) - 26:12
Authors Lei Zhang, Lei Zou and Peng Sun*
Abstract Background: The purpose of this study was to explore the clinical value of miR-378c and its target gene YY1 in gastric cancer.
Methods: The TCGA database was employed to analyse miR-378c expression in gastric cancer. qRT-PCR was applied to identify miR-378c and YY1 in tissues and serum of patients sufering from gastric cancer. The association of miR-378c with the clinical data of patients with gastric cancer was analysed. Receiver operating characteristics (ROC) curve analysis was used to determine the diagnostic value of miR-378c and YY1 in gastric cancer, and analyse the relationship between miR-378c and YY1 and patients’ survival. Pearson’s test was applied to determine the association between miR-378c and YY1 in tissue and serum of patients. Dual-Luciferase Reporter assay was employed to examine the targeting association between miR-378c and YY1. Finally, independent prognostic factors was determined in patients with gastric cancer using Cox regression analysis.
Results: In the TCGA database, miR-378c was weakly expressed in gastric cancer. Overall, patients with low expression had a lower survival rate. The expression of miR-378c decreased and the expression of YY1 increased in cancer tissues and serum of tumour patients. In patients with low expression of miR-378c the tumour size was ≥5 cm. Low diferentiation, high TNM staging and lymph node invasion rate increased signifcantly, but the 5-year survival rate decreased in the patients. miR-378c and YY1 had better diagnostic value in gastric cancer. TargetScan, miRDB, starBase and miRTarBase predicted that YY1 was a potential gene of miR-378c, and the Dual-Luciferase Reporter assay revealed that there was a targeting relationship between the two, which was proved by correlation analysis. Multivariate Cox analysis revealed that diferentiation, TNM staging and miR-378c were independent prognostic factors for patients.
Conclusions: MiR-378c is weakly expressed in gastric cancer patients and may be considered as a promising diagnostic and prognostic indicator for gastric cancer.
Keywords miR-378c, YY1, Gastric cancer, Prognosis
Address and Contact Information Department of Gastroenterology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo 255000, Shandong, China
*Corresponding author: ptl4bb@163.com
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No. 13 DOI: 10.1186/s11658-021-00257-w Volume 26 (2021) - 26:13
Authors Meysam Moghbeli*
Abstract Background: Cancer, as one of the main causes of human deaths, is currently a signifcant global health challenge. Since the majority of cancer-related deaths are associated with late diagnosis, it is necessary to develop minimally invasive early detection markers to manage and reduce mortality rates. MicroRNAs (miRNAs), as highly conserved non-coding RNAs, target the specifc mRNAs which are involved in regulation of various fundamental cellular processes such as cell proliferation, death, and signaling pathways. MiRNAs can also be regulated by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). They are highly stable in body fuids and have tumor-specific expression profles, which suggest their suitability as efcient non-invasive diagnostic and prognostic tumor markers. Aberrant expression of miR-338 has been widely reported in diferent cancers. It regulates cell proliferation, migration, angiogenesis, and apoptosis in tumor cells.
Main body: In the present review, we have summarized all miR-338 interactions with other non-coding RNAs (ncRNAs) and associated signaling pathways to clarify the role of miR-338 during tumor progression.
Conclusions: It was concluded that miR-338 mainly functions as a tumor suppressor in diferent cancers. There were also signifcant associations between miR-338 and other ncRNAs in tumor cells. Moreover, miR-338 has a pivotal role during tumor progression using the regulation of WNT, MAPK, and PI3K/AKT signaling pathways. This review highlights miR-338 as a pivotal ncRNA in biology of tumor cells.
Keywords Non-coding RNA, MicroRNA, MiR-338, Cancer, Biomarker
Address and Contact Information Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
*Correspondence: Meysam_moghbeli@yahoo.com; moghbelim@mums.ac.ir
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No. 14 DOI: 10.1186/s11658-021-00258-9 Volume 26 (2021) - 26:14
Authors Shahad W. Kattan1, Yahya H. Hobani2, Sameerah Shaheen3, Sara H. Mokhtar4, Mohammad H. Hussein5, Eman A. Toraih5,6, Manal S. Fawzy7,8* and Hussein Abdelaziz Abdalla9,10
Abstract Background: The expression signature of deregulated long non-coding RNAs (lncRNAs) and related genetic variants is implicated in every stage of tumorigenesis, progression, and recurrence. This study aimed to explore the association of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene expression and the rs2383207A>G intronic variant with breast cancer (BC) risk and prognosis and to verify the molecular role and networks of this lncRNA in BC by bioinformatics gene analysis.
Methods: Serum CDKN2B-AS1 relative expression and rs2383207 genotypes were determined in 214 unrelated women (104 primary BC and 110 controls) using real-time PCR. Sixteen BC studies from The Cancer Genome Atlas (TCGA) including 8925 patients were also retrieved for validation of results.
Results: CDKN2B-AS1 serum levels were upregulated in the BC patients relative to controls. A/A genotype carriers were three times more likely to develop BC under homozygous (OR=3.27, 95% CI 1.20–8.88, P=0.044) and recessive (OR=3.17, 95% CI 1.20–8.34, P=0.013) models. G/G homozygous patients had a higher expression level [median and quartile values were 3.14 (1.52–4.25)] than A/G [1.42 (0.93–2.35)] and A/A [1.62 (1.33–2.51)] cohorts (P=0.006). The Kaplan–Meier curve also revealed a higher mean survival duration of G/G cohorts (20.6 months) compared to their counterparts (A/A: 15.8 and A/G: 17.2 months) (P<0.001). Consistently, BC data sets revealed better survival in cohorts with high expression levels (P=0.003). Principal component analysis (PCA) showed a deviation of patients who had shorter survival towards A/A and A/G genotypes, multiple lesions, advanced stage, lymphovascular invasion, and HER2+ receptor staining. Ingenuity Pathway Analysis (IPA) showed key genes highly enriched in BC with CDKN2B-AS1.
Conclusions: The findings support the putative role of CDKN2B-AS1 as an epigenetic marker in BC and open a new avenue for its potential use as a therapeutic molecular target in this type of cancer.
Keywords Breast cancer, CDKN2B-AS1, Gene expression, Long non-coding RNA, Single nucleotide polymorphism, Survival
Address and Contact Information 1 Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia
2 Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia.
3 Anatomy Department and Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4 Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
5 Department of Surgery, Tulane University, School of Medicine, New Orleans, LA, USA.
6 Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
7 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
8 Department of Biochemistry, College of Medicine, Northern Border University, Arar, Saudi Arabia.
9 Department of Medical Biochemistry, Faculty of Medicine, Taibah University, Medina, Saudi Arabia.
10 Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
*Corresponding author: manal2_khashana@ymail.com
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No. 15 DOI: 10.1186/s11658-021-00259-8 Volume 26 (2021) - 26:15
Authors Bing Sun1†, Rongmei Qu1†, Tingyu Fan1†, Yuchao Yang1, Xin Jiang1, Asmat Ullah Khan1, Zhitao Zhou2, Jingliao Zhang3, Kuanhai Wei4, Jun Ouyang1* and Jingxing Dai1*
Abstract Background: Actin is an essential cellular protein that assembles into microflaments and regulates numerous processes such as cell migration, maintenance of cell shape, and material transport.
Methods: In this study, we explored the efect of actin polymerization state on the osteogenic diferentiation of human adipose-derived stem cells (hASCs). The hASCs were treated for 7 days with diferent concentrations (0, 1, 5, 10, 20, and 50 nM) of jasplakinolide (JAS), a reagent that directly polymerizes F-actin. The efects of the actin polymerization state on cell proliferation, apoptosis, migration, and the maturity of focal adhesion-related proteins were assessed. In addition, western blotting and alizarin red staining assays were performed to assess osteogenic diferentiation.
Results: Cell proliferation and migration in the JAS (0, 1, 5, 10, and 20 nM) groups were higher than in the control group and the JAS (50 nM) group. The FAK, vinculin, paxillin, and talin protein expression levels were highest in the JAS (20 nM) group, while zyxin expression was highest in the JAS (50 nM) group. Western blotting showed that osteogenic diferentiation in the JAS (0, 1, 5, 10, 20, and 50 nM) group was enhanced compared with that in the control group, and was strongest in the JAS (50 nM) group.
Conclusions: In summary, our data suggest that the actin polymerization state may promote the osteogenic diferentiation of hASCs by regulating the protein expression of focal adhesion-associated proteins in a concentration-dependent manner. Our findings provide valuable information for exploring the mechanism of osteogenic diferentiation in hASCs.
Keywords Human adipose-derived stem cells, Actin polymerization, Osteogenic diferentiation, Jasplakinolide, Cell proliferation and migration
Address and Contact Information 1 Guangdong Provincial Key Laboratory of Medical Biomechanics and Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, China
2 Central Laboratory, Southern Medical University, Guangzhou, China.
3 Department of Foot and Ankle Surgery, Henan Luoyang Orthopedic Hospital, Zhengzhou, China.
4 Division of Orthopaedics and Traumatology, Department of Orthopaedics, Guangdong Provincial Key Laboratory of Bone and Cartilage Regeneration Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
*Corresponding author: jouyang@smu.edu.cn; daijx@smu.edu.cn
Bing Sun, Rongmei Qu, and Tingyu Fan contributed equally to this article
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No. 16 DOI: 10.1186/s11658-021-00260-1 Volume 26 (2021) - 26:16
Authors Tasuku Nishino1, Tsuyoshi Oshika2, Moriatsu Kyan2 and Hiroaki Konishi2*
Abstract Background: In mammals, there are two subtypes of Grb2-associated regulator of Erk/MAPK (GAREM), an adaptor protein that functions downstream of the cell growth factor receptor. GAREM1 is ubiquitously expressed, whereas GAREM2 is mainly expressed in the brain. However, the precise mechanism of the translocation of each GAREM subtype in growth factor-stimulated cells is still unclear.
Methods: In this study, immunofuorescence staining with specifc antibodies against each GAREM subtype and time-lapse analysis using GFP fusion proteins were used to analyze the subcellular localization of each GAREM subtype in a cell growth stimulus-dependent manner. We also biochemically analyzed the correlation between its sub-cellular localization and tyrosine phosphorylation of GAREM2.
Results: We found that endogenously and exogenously expressed GAREM2 specifcally aggregated and formed granules in NGF-stimulated PC-12 cells and in EGF-stimulated COS-7 cells. Based on the observed subcellular localizations of chimeric GAREM1 and GAREM2 proteins, a glycine-rich region, which is present only in GAREM2, is required for the observed granule formation. This region also regulates the degree of EGF-stimulation-dependent tyrosine phosphorylation of GAREM2.
Conclusions: Our results, showing that aggregation of GAREM2 in response to EGF stimulation is dependent on a glycine-rich region, suggest that GAREM2 aggregation may be involved in neurodegenerative diseases.
Keywords Adaptor protein, Protein aggregation, Glycine-rich, EGF receptor, Tyrosine phosphorylation
Address and Contact Information 1 Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
2 Division of Bioscience and Biotechnology Department of Agricultural and Life Sciences, Faculty of Agriculture, Shinshu University, 8304 Minamiminowa, Nagano 399-4598, Japan.
*Corresponding author: hkonishi@shinshu-u.ac.jp
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No. 17 DOI:10.1186/s11658-021-00254-z Volume 26 (2021) - 26:17
Authors Jianan Zhao1, Yiyang Hu2,3,4* and Jinghua Peng1,3,4*
Abstract Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although signifcant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.
Keywords Metabolic dysfunction-associated fatty liver disease, Apoptosis, Necroptosis, Autophagy, Pyroptosis, Ferroptosis
Address and Contact Information 1 Institute of Liver Diseases, Shuguang Hospital Afliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
2 Institute of Clinical Pharmacology, Shuguang Hospital afliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
3 Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong District, Shanghai 201203, China
4 Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China
*Corresponding author: yyhuliver@163.com; pengjinghua2004@163.com
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No. 18DOI: 10.1186/s11658-021-00262-z Volume 26 (2021) - 26:18
Authors Alicja Koscielny1, Ewa Liszewska1, Katarzyna Machnicka1, Michalina Wezyk1,2, Katarzyna Kotulska3 and Jacek Jaworski1*
Abstract Background: Mammalian/mechanistic target of rapamycin (mTOR) complexes are essential for cell proliferation, growth, diferentiation, and survival. mTORC1 hyperactivation occurs in the tuberous sclerosis complex (TSC). mTORC1 localizes to the surface of lysosomes, where Rheb activates it. However, mTOR was also found on the endoplasmic reticulum (ER) and Golgi apparatus (GA). Recent studies showed that the same inputs regulate ER-to-GA cargo transport and mTORC1 (e.g., the level of amino acids or energy status of the cell). Nonetheless, it remains unknown whether mTOR contributes to the regulation of cargo passage through the secretory pathway.
Methods: The retention using selective hooks (RUSH) approach was used to image movement of model cargo (VSVg) between the ER and GA in various cell lines in which mTOR complexes were inhibited. We also investigated VSVg trafcking in TSC patient fibroblasts.
Results: We found that mTOR inhibition led to the overall enhancement of VSVg transport through the secretory pathway in PC12 cells and primary human fbroblasts. Also, in TSC1-defcient cells, VSVg transport was enhanced.
Conclusions: Altogether, these data indicate the involvement of mTOR in the regulation of ER-to-GA cargo transport and suggest that impairments in exocytosis may be an additional cellular process that is disturbed in TSC.
Keywords MTOR, Endoplasmic reticulum, Golgi apparatus, VSVg, Tuberous sclerosis complex, Retention using selective hooks
Address and Contact Information 1 International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 04-421 Warsaw, Poland.
2 Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre of the Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland.
3 Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland.
*Corresponding author: jaworski@iimcb.gov.pl
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No. 19 DOI: 10.1186/s11658-021-00263-y Volume 26 (2021) - 26:19
Authors Lijiang Ji1,2†, Weixing Shen2,4†, Feng Zhang2, Jie Qian2, Jie Jiang1,2, Liping Weng1, Jiani Tan2,4, Liu Li2,4, Yugen Chen2,4, Haibo Cheng2,4* and Dongdong Sun2,3*
Abstract Background: Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side efects than traditional chemotherapy. Here, we explore the pharmacological efects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer.
Methods: The efects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms.
Results: Worenine somewhat altered the glucose metabolism and glycolysis (Warburg efect) of cancer cells. Its anti-cancer efects and capability to reverse the Warburg efect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist).
Conclusion: It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg efect.
Keywords Worenine, Warburg efect, Colon cancer, HIF-1α, Glycolysis
Address and Contact Information 1 Changshu TCM Hospital Afliated to Nanjing University of Chinese Medicine, Changshu 215500, China.
2 Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing 210023, China.
3 School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
4 The First School of Clinical Medicine, The Afliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
*Corresponding author: hbcheng_njucm@163.com; sundd@njucm.edu.cn
Lijiang Ji and Weixing Shen have contributed equally to this work.
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No. 20 DOI: 10.1186/s11658-021-00268-7 Volume 26 (2021) - 26:20
Authors Xiaomei Sun1,2, Lingtong Hou3, Chunping Qiu2,4 and Beihua Kong2,4*
Abstract Background: Several studies have shown the crucial role of miR-501 in regulating cellular pathology in various cancers. However, the function and expression of miR-501 in endometrial cancer (EC) remain obscure.
Methods: The expression of miR-501 was determined using quantitative real-time PCR. MTT assay, colony formation assay and cell cycle analysis were used to evaluate the proliferation ability. Migration and invasion were assessed using transwell assay. Tumor formation in nude mice was used to observe the efects of miR-501 on cell proliferation and migration in vivo. Luciferase assay, quantitative real-time PCR and western blot were applied to determine that HOXD10 was the target gene of miR-501.
Results: In this study, we observed signifcantly up-regulated expression of miR-501 in endometrial cancer, which correlated with higher pelvic lymph node metastasis and shorter overall survival in high-grade endometrial cancer. High expression of miR-501 was also found in the copy-number-high group than other groups. Moreover, in vitro and in vivo assay showed that overexpression of miR-501 can promote proliferation and metastasis. Mechanistically, we found that miR-501 promotes tumor progression by directly targeting HOXD10. Further study also indicated that miR-501 overexpression can activate the AKT/mTOR pathway.
Conclusions: MiR-501, which functions as an oncomir in endometrial cancer, might be a potential therapeutic target in high grade endometrial cancer.
Keywords MiR-501, Endometrial cancer, Proliferation, Metastasis, HOXD10
Address and Contact Information 1 Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China.
2 Key Laboratory of Gynecologic Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, People’s Republic of China.
3 Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China.
4 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan 250012, Shandong, People’s Republic of China.
*Corresponding author: kongbeihua@sdu.edu.cn
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No.  21DOI: 10.1186/s11658-021-00266-9 Volume 26 (2021) - 26:21
Authors Qiudan Chen1†, Weifeng Wang2†, Shuying Chen3†, Xiaotong Chen3 and Yong Lin3*
Abstract Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the efects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory efect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and fnally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while ofering a possible target for treating human glioma in the future.
Keywords Glioma, miRNA, miR-29a, p53, MDM2
Address and Contact Information 1 The Department of Central Laboratory, Clinical Laboratory, Jing’an District Center Hospital of Shanghai, Fudan University, Shanghai 200040, China.
2 Department of Central Laboratory, Clinical Medicine Scientifc and Technical Innovation Park, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200435, China.
3 Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 20040, China.
*Corresponding author: leeyoug@163.com
Qiudan Chen, Weifeng Wang, Shuying Chen have contributed equally to this paper.
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No.  22DOI: 10.1186/s11658-021-00269-6 Volume 26 (2021) - 26:22
Authors Xiaozhong Zhou1,2, Wangyang Xu1, Yeyang Wang1, Hui Zhang1, Li Zhang1, Chao Li1, Shun Yao1, Zixiang Huang1, Lishan Huang1 and Dixin Luo1*
Abstract Background: Improved chondrogenic diferentiation of mesenchymal stem cells (MSCs) by genetic regulation is a potential method for regenerating articular cartilage. MiR-127-5p has been reported to promote cartilage diferentiation of rat bone marrow MSCs (rMSCs); however, the regulatory mechanisms underlying hypoxia-stimulated hondrogenic diferentiation remain unknown.
Methods: rMSCs were induced to undergo chondrogenic diferentiation under normoxic or hypoxic conditions. Expression of lncRNA DNM3OS, miR-127-5p, and GREM2 was detected by quantitative real-time PCR. Proteoglycans were detected by Alcian blue staining. Western blot assays were performed to examine the relative levels of GREM2 and chondrogenic diferentiation related proteins. Luciferase reporter assays were performed to assess the association among DNM3OS, miR-127-5p, and GREM2.
Results: MiR-127-5p levels were upregulated, while DNM3OS and GREM2 levels were downregulated in rMSCs induced to undergo chondrogenic diferentiation, and those changes were attenuated by hypoxic conditions (1% O2). Further in vitro experiments revealed that downregulation of miR-127-5p reduced the production of proteoglycans and expression of chondrogenic diferentiation markers (COL1A1, COL2A1, SOX9, and ACAN) and osteo/chondrogenic markers (BMP-2, p-SMAD1/2). MiR-127-5p overexpression produced the opposite results in rMSCs induced to undergo chondrogenic diferentiation under hypoxic conditions. GREM2 was found to be a direct target of miR-127-5p, which was suppressed in rMSCs undergoing chondrogenic diferentiation. Moreover, DNM3OS could directly bind to miR-127-5p and inhibit chondrogenic differentiation of rMSCs via regulating GREM2.
Conclusions: Our study revealed a novel molecular pathway (DNM3OS/miR-127-5p/GREM2) that may be involved in hypoxic chondrogenic diferentiation.
Keywords Mesenchymal stem cells, Chondrogenic diferentiation, Hypoxic condition, miR-127-5p, GREM2, DNM3OS
Address and Contact Information 1 The Spine Department, Orthopaedic Center, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Haizhu District, Guangzhou 510317, Guangdong, People’s Republic of China
2 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
*Correspondinga author: luodixin177@163.com
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No.  23DOI: 10.1186/s11658-021-00267-8 Volume 26 (2021) - 26:23
Authors Yanning Huang1, Qiaolin Wen2, Jinfeng Huang3, Man Luo1, Yousheng Xiao1, Ruikang Mo3 and Jin Wang1*
Abstract Background: Manganese overexposure can induce neurotoxicity, lead to manganism and result in clinical manifestations similar to those of parkinsonism. However, the underlying molecular mechanism is still unclear. This study demonstrated that MnCl2 induces mitophagy and leads to neurotoxicity by promoting BNIP3-mediated reactive oxygen species (ROS) generation.
Methods: Human neuroblastoma SH-SY5Y cells were used throughout our experiments. Cell viability was detected by cell proliferation/toxicity test kits. Mitochondrial membrane potential was measured by fow cytometry. ROS generation was detected using a microplate reader. Protein levels were evaluated by Western blot. Transmission electron microscopy was used to evaluate mitochondrial morphology. Co-immunoprecipitation was used to verify the interaction between BNIP3 and LC3.
Results: MnCl2 led to loss of mitochondrial membrane potential and apoptosis of SH-SY5Y cells by enhancing expression of BNIP3 and conversion of LC3-I to LC3-II. Moreover, MnCl2 reduced expression of the mitochondrial marker protein TOMM20 and promoted interaction between BNIP3 and LC3. The results also indicated that a decrease in BNIP3 expression reduced the mitochondrial membrane potential loss, attenuated apoptosis and reduced mitochondrial autophagosome formation in SH-SY5Y cells after MnCl2 treatment. Finally, we found that manganese-induced ROS generation could be reversed by the antioxidant N-acetyl cysteine (NAC) or silencing BNIP3 expression.
Conclusions: BNIP3 mediates MnCl2-induced mitophagy and neurotoxicity in dopa-minergic SH-SY5Y cells through ROS. Thus, BNIP3 contributes to manganese-induced neurotoxicity by functioning as a mitophagy receptor protein.
Keywords Manganese, Neurotoxicity, Mitophagy, BNIP3, Oxidative stress
Address and Contact Information 1 Department of Neurology, The First Afliated Hospital of Guangxi Medical University, Nanning 530021, China
2 Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545005, China.
3 Department of Neurology, First Peoples Hospital of Nanning, Nanning 530021, China.
*Corresponding author: Wangjin72@126.com
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No.  24DOI: 10.1186/s11658-021-00265-w Volume 26 (2021) - 26:24
Authors Yanfen Lian, Dongxiao Jiang and Jiangtao Sun*
Abstract Background: The suppressive efects of miR-33a-5p have been reported in colorectal cancer and lung cancer. However, the functional role of miR-33a-5p in pancreatic ductal adenocarcinoma (PDAC) has not yet been elucidated.
Methods: The expression of miR-33a-5p was determined using reverse-transcription quantitative PCR (RT-qPCR) in PDAC tissues and cell lines. The association between miR-33a-5p expression and clinical categorical parameters was analyzed by the chi-square test. Cell proliferation was analyzing by Cell Counting Kit -8 (CCK-8) assay. Transwell assay was utilized to assess cell migration and invasion. The interactions between miR-33a-5p and RAP2A were verifed by luciferase reporter assay, RT-qPCR, western blot analysis and RNA immunoprecipitation (RIP) assay.
Results: Here, we observed for the frst time that miR-33a-5p expression level was signifcantly decreased in PDAC tissues and cell lines. There was a signifcant association between decreased miR-33a-5p expression and TNM stage or lymph node metastasis. Overexpression of miR-33a-5p signifcantly inhibited SW1990 and PANC-1 cell proliferation, migration and invasion. Knockdown of miR-33a-5p remarkedly promoted cell proliferation, migration and invasion in BxPC-3 and ASPC-1. Mechanistically, RAP2A was confrmed as the target of miR-33a-5p in PDAC cells. Moreover, RAP2A overexpression abolished miR-33a-5p-mediated suppressive efects on SW1990 and PANC-1 cells.
Conclusions: Taken together, these results suggest that miR-33a-5p exerted tumor suppressive efects on PDAC cells by targeting RAP2A, which might provide a new theoretical basis for the clinical treatment of PDAC.
Keywords PDAC, miR-33a-5p, RAP2A, Proliferation, Migration, Invasion
Address and Contact Information Department of Oncology, Weihai Central Hospital Afliated to Medical College of Qingdao University, No.3, West Mishan East Road, Weihai, Shandong, China
*Corresponding author: sun_jiangtao2016@yeah.net
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No.  25DOI: 10.1186/s11658-021-00270-z Volume 26 (2021) - 26:25
Authors Xuan Xiong1,2, Changchun Liu1, Meiren Shen1, Qian Yang1, Qiang Zhao3, Xiaoyan Li4, Xiaoshi Zhong2,5* and Zhiwei Wang4*
Abstract Background: Diabetic nephropathy is one of the most important complications in patients with diabetes. The etiology and pathogenesis of diabetic nephropathy remain unclear. Several studies have indicated that circular RNAs (circRNAs) play crucial regulatory roles in numerous human diseases and normal physiology; however, to date, no study has focused on the comprehensive expression profle of circRNAs in the kidneys of diabetic mice. Therefore, we aimed to identify diferentially expressed circRNAs in diabetic mouse kidneys to explore the possible roles of dysregulated circRNAs in diabetic nephropathy development.
Results: Diabetic BKS-Leprem2Cd479/Nju (BKS-DB/Nju) mice and their nondiabetic wild-type littermates of C57BL/KsJ wild-type (WT) mice were used as experimental animals. Among all circRNAs identifed by high-throughput RNA sequencing, four circRNAs were upregulated and ten were downregulated in diabetic mouse kidneys compared to those in nondiabetic mouse kidneys. After verifcation using quantitative reverse transcriptase polymerase chain reaction assays, we found that circR_1084, circR_182, circR_4, circR_50, circR_596, circR_897, and circR_203 were downregulated, whereas circR_627, circR_628, circR_735, and circR_801 were upregulated in the renal tissues of 8- and 16-week-old BKS-DB/Nju mice compared to those in WT mice.
Conclusion: We studied the circRNA expression profle in the kidneys of diabetic mice. Diferentially expressed circRNAs may be useful as candidate biomarkers for diabetic nephropathy. Collectively, our results provide a novel theoretical basis for further investigation of the regulatory roles of circRNA in the etiology and pathogenesis of diabetic nephropathy.
Keywords Circular RNA, Diabetic nephropathy, miRNA target, Gene ontology analysis, Pathway analysis
Address and Contact Information 1 Department of Nephrology, The Afliated Shunde Hospital of Guangzhou Medical University, Foshan 528315, China.
2 Department of Nephrology, Guangzhou Red Cross Hospital, Medical School of Jinan University, Guangzhou 510220, China.
3 Department of Cardiology, The Afliated Shunde Hospital of Guangzhou Medical University, Foshan 528315, China.
4 Laboratory Medicine Centre, The Afliated Shunde Hospital of Guangzhou Medical University, Foshan 528315, China.
5 Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital, Medical School of Jinan University, Guangzhou 510220, China.
* Corresponding author: zxshhyy@ext.jnu.edu.cn; wangzhiwei_001@sina.com
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No.  26DOI: 10.1186/s11658-021-00271-y Volume 26 (2021) - 26:26
Authors Dazhi Fu1*, Chunxiao Wang2, Lei Yu1 and Rui Yu1
Abstract Background: Currently, resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy. Here, we sought to investigate the function of activating transcription factor 3 (ATF3) n GC chemoresistance.
Methods: Expression of ATF3 was determined in GC cell lines (MNK45, SGC7901, and BGC823) and cisplatin (DDP)-resistant cells (SGC7901/DDP and BGC823/DDP). Biological informatics was performed to analyze ATF3 expression and prognosis in GC patients. Cisplatin resistance was evaluated. Ferroptosis was detected after ATF3 transfection of cells. The underlying molecular mechanism was also investigated.
Results: Transcripts of ATF3 were decreased in GC cells and GC tissues. Kaplan–Meier plotter analysis revealed that ATF3 expression was positively related to the overall survival of GC patients. In particular, lower levels of ATF3 were observed in cisplatin-resistant SGC7901/DDP and BGC823/DDP relative to their parental cells. Notably, ATF3 elevation sensitized cisplatin-resistant cells to cisplatin. Mechanically, compared with parental cells, SGC7901/DDP and BGC823/DDP cells exhibited lower ferroptosis evident by lower ROS, MDA and lipid peroxidation and higher intracellular GSH levels. However, ATF3 elevated ferroptosis in SGC7901/DDP and BGC823/DDP cells. Intriguingly, ATF3 overexpression together with ferroptosis activator erastin or RSL3 treatment further enhanced ferroptosis and cisplatin resistance; however, the ferroptosis suppressor liproxstatin-1 reversed the function of ATF3 in ferroptosis and cisplatin resistance. Additionally, cisplatin-resistant cells exhibited stronger activation of Nrf2/Keap1/xCT signaling relative to parental cells, which was restrained by ATF3 up-regulation. Importantly, restoring Nrf2 signaling overturned ATF3-mediated ferroptosis and cisplatin resistance.
Conclusion: ATF3 may sensitize GC cells to cisplatin by induction of ferroptosis via blocking Nrf2/Keap1/xCT signaling, supporting a promising therapeutic approach for overcoming chemoresistance in GC.
Keywords Gastric cancer, ATF3, Cisplatin resistance, Ferroptosis, Nrf2/Keap1 signaling
Address and Contact Information 1 Department of General Surgery, First Afliated Hospital of China Medical University, Liaoning Province Shenyang City Heping District Nanjingbei Road 155, Shenyang 110001, Liaoning, People’s Republic of China.
2 Department of General Surgery, Liaoning Health Industry Group, Benxi Iron & Steel Group, General Hospital, Benxi 117000, Liaoning, People’s Republic of China.
* Corresponding author: fudazhihospital@yandex.com
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No.  27DOI: 10.1186/s11658-021-00264-x Volume 26 (2021) - 26:27
Authors Jia Ni1*, Zhen Huang2 and Dan Wang1*
Abstract Background: Although lncRNA TP73-AS1 has been shown to play important roles in various human diseases, its function in atherosclerosis (AS) remains unclear.
Methods: Human aortic endothelial cells (HAECs) were treated with 50 μg/ml oxidized low-density lipoprotein (ox-LDL) to establish an atherosclerotic cell model. The expression of TP73-AS1, miR-654-3p and AKT3 was detected by qRT-PCR. Cell functions were evaluated CCK-8 assay and fow cytometry. The protein levels of apoptosis-related proteins were evaluated by western blot. The binding relationship among TP73-AS1, miR-654-3p and AKT3 was determined by bioinformatics analysis and luciferase reporter assay.
Results: TP73-AS1 was upregulated and miR-654-3p was downregulated in ox-LDL treated HAECs. TP73-AS1 silencing and miR-654-3p mimics decreased the viability and inhibited apoptosis of ox-LDL treated HAECs, decreased the expression levels of c-caspase-9, c-caspase-3 and Bax, and increased Bcl-2 expression. In addition, miR-654-3p inhibitor signifcantly reversed the inhibitory efects of si-TP73-AS1 on cell viability and apoptosis. TP73-AS1 could positively regulate AKT3 through directly sponging miR-654-3p.
Conclusion: TP73-AS1 promoted apoptosis of ox-LDL stimulated endothelial cells by targeting the miR-654-3p/AKT3 axis, suggesting that TP73-AS1 might be a potential target for AS treatment.
Keywords TP73-AS1, miR-654-3p, AKT3, Atherosclerosis, Apoptosis
Address and Contact Information 1 Stomatological Hospital, Southern Medical University, No. 366 Jiangnan Avenue South, Haizhu District, Guangzhou City, Guangdong Province, People’s Republic of China.
2 Peking University School of Stomatology, Beijing 100081, People’s Republic of China.
*Corresponding author: rx9705@163.com; DanWangHaizhu@163.com
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No.  28DOI: 10.1186/s11658-021-00261-0 Volume 26 (2021) - 26:28
Authors Guoying Zhang1,2, Cheng Xue1,3 and Yiming Zeng1*
Abstract Background: We have previously found that β-elemene could inhibit the viability of airway granulation fbroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efcacy of β-elemene in vitro and in vivo.
Methods: Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a β-elemene-treated primary cell model and to construct a β-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in β-elemene’s regulation of the target pathway and cell viability. Additionally, in a β-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efcacy and further verify its mechanism of action.
Results: The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in β-elemene-treated airway granulation fbroblasts; β-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fbroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of β-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that β-elemene’s efects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro fndings.
Conclusions: MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates β-elemene-induced cell cycle arrest and apoptosis of airway granulation fbroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.
Keywords Tracheal stenosis, Fibroblast, β-elemene, CeRNA, ILK/Akt pathway
Address and Contact Information 1 Department of Pulmonary and Critical Care Medicine, Respiratory Medicine Center of Fujian Province, The Second Afliated Hospital of Fujian Medical University, Zhongshan North Road No.34, Licheng District, Quanzhou, Fujian, China.
2 Department of Pulmonary and Critical Care Medicine, Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian, China.
3 Department of Pulmonary and Critical Care Medicine, The First Afliated Hospital of Xiamen University, Xiamen, Fujian, China.
*Corresponding author: ymzeng08@163.com
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No.  29DOI: 10.1186/s11658-021-00272-x Volume 26 (2021) - 26:29
Authors Päivi Ylä‐Anttila1,2,3*
Abstract Activation of autophagy is part of the innate immune response during viral infections. Autophagy involves the sequestration of endogenous or foreign components from the cytosol within double-membraned vesicles and the delivery of their content to the lysosomes for degradation. As part of innate immune responses, this autophagic elimination of foreign components is selective and requires specialized cargo receptors that function as links between a tagged foreign component and the autophagic machinery. Pathogens have evolved ways to evade their autophagic degradation to promote their replication, and recent research has shown autophagic receptors to be an important and perhaps previously overlooked target of viral autophagy inhibition. This is a brief summary of the recent progress in knowledge of virus-host interaction in the context of autophagy receptors.
Keywords Autophagy, Infection, Receptor, Viruses, Cargo, Xenophagy
Address and Contact Information 1 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
2 Present Address: Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Institutet, Stockholm, Sweden.
3 Present Address: Division of Neurology, Karolinska University Hospital, Stockholm, Sweden.
*Corresponding author: paivi.ylaanttila@gmail.com
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No.  30DOI: 10.1186/s11658-021-00273-w Volume 26 (2021) - 26:30
Authors Shabnam Babazadeh1, Seyed Mahdi Nassiri1*, Vahid Siavashi1, Mohadeseh Sahlabadi1, Mostafa Hajinasrollah2 and Mohamad Zamani‐Ahmadmahmudi3
Abstract Background: Phenotypic and functional heterogeneity of macrophages is known to be the main reason for their ability to regulate infammation and promote tumorigenesis. Mesenchymal stem cells (MSCs) are one of the principal cells commonly found in the tumor stromal niche, with capability of macrophage phenotypic switching. The objective of this study was to evaluate the role of C-X-C motif chemokine ligand 12 (CXCL12) produced by marrow-derived MSCs in the phenotypic and functional pattern of bone marrow-derived macrophages (BMDMs).
Methods: First, the CRISPR/Cas9 system was used for the CXCL12 gene knock-out in MSCs. Then, coculture systems were used to investigate the role of MSCsCXCL12−/− and MSCsCXCL12+/+ in determination of macrophage phenotype. To further analyze the role of the MSC-derived CXCL12 niche, cocultures of 4T1 mammary tumor cells and macrophages primed with MSCsCXCL12−/− or MSCsCXCL12+/+ as well as in-vivo limiting dilution assays were performed.
Results: Our results revealed that the expression of IL-4, IL-10, TGF-β and CD206 as M2 markers was signifcantly increased in macrophages co-cultured with MSCsCXCL12+/+, whereas the expression of IL-6, TNF-α and iNOS was conversely decreased. The number and size of multicellular tumor spheroids were remarkably higher when 4T1 cells were cocultured with MSCCXCL12+/+-induced M2 macrophages. We also found that the occurrence of tumors was signifcantly higher in coinjection of 4T1 cells with MSCCXCL12+/+-primed macrophages. Tumor initiating cells were signifcantly decreased after coinjection of 4T1 cells with macrophages pretreated with MSCsCXCL12−/−.
Conclusions: In conclusion, our fndings shed new light on the role of MSC-derived CXCL12 in macrophage phenotypic switching to M2, afecting their function in tumorigenesis.
Keywords Mesenchymal stem cells (MSCs), Macrophage, Cytokine, C-X-C motif chemokine ligand 12 (CXCL12), Phagocytosis, Tumor microenvironment
Address and Contact Information 1 Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
2 Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
3 Department of Clinical Science, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.
*Corresponding author: nasirim@ut.ac.ir
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No.  31DOI: 10.1186/s11658-021-00274-9 Volume 26 (2021) - 26:31
Authors Meng Li, Di Zhong* and Guozhong Li
Abstract Developmental endothelial locus-1 (Del-1) is a secretory, multifunctional domain protein. It can bind to integrins and phosphatidylserine. As a local tissue signal, it plays a regulatory role in the cancer microenvironment and infammation. Del-1 has destructive efects in most cancers and is associated with the progression and invasion of some cancers. In contrast, Del-1 also plays a protective role in infammation. Del-1 regulates infammation by regulating the generation of neutrophils in bone marrow, inhibiting the recruitment and migration of neutrophils and accelerating the clearance of neutrophils by macrophages. Del-1 and IL-17 are reciprocally regulated, and their balance maintains immune system homeostasis. Del-1 is expected to become a new therapeutic target for infammatory disorders such as multiple sclerosis.
Keywords Del-1, Local tissue signals, Cancer microenvironment, Infammation resolution, Immunity homeostasis
Address and Contact Information Department of Neurology, First Afliated Hospital of Harbin Medical University, No. 23 Youzheng Road, Harbin 150001, Heilongjiang, China
*Corresponding author: bioinfo@hrbmu.edu.cn; sjnkzhongdi@163.com
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No.  32DOI: 10.1186/s11658-021-00276-7 Volume 26 (2021) - 26:32
Authors Jianan Zhao1, Yu Zhao1,3,4, Yiyang Hu2,3,4* and Jinghua Peng1,3,4*
Abstract In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological efects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting infammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.
Keywords GPCR, GPR119, Incretins, Metabolic (dysfunction)-associated fatty liver disease, Liver disease
Address and Contact Information 1 Institute of Liver Diseases, Shuguang Hospital Afliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
2 Institute of Clinical Pharmacology, Shuguang Hospital Afliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
3 Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine), Ministry of Education, 528 Zhangheng Road, Pudong District, Shanghai 201203, China.
4 Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
*Corresponding author: yyhuliver@163.com; pengjinghua2004@163.com
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No.  33DOI: 10.1186/s11658-021-00275-8 Volume 26 (2021) - 26:33
Authors An Yang1, Xin Liu2, Ping Liu1, Yunzhang Feng1, Hongbo Liu1, Shen Gao3, Limin Huo3, Xinyan Han1, Jurong Wang1 and Wei Kong1*
Abstract Background: Long noncoding RNA (lncRNA), urothelial carcinoma-associated 1 (UCA1) is aberrantly expressed in multiple cancers and has been verifed as an oncogene. However, the underlying mechanism of UCA1 in the development of gastric cancer is not fully understood. In the present study, we aimed to identify how UCA1 promotes gastric cancer development.
Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data were used to analyze UCA1 and myosin VI (MYO6) expression in gastric cancer. Western blot and quantitative real-time PCR (QPCR) were performed to test the expression level of the UCA1/miR-145/MYO6 axis in gastric cancer cell lines and tissues. The roles of the UCA1/miR-145/MYO6 axis in gastric cancer in vitro and in vivo were investigated by CCK-8 assay, fow cytometry, siRNAs, immunohistochemistry, and a mouse xenograft model. The targeted relationship among UCA1, miR-145, and MYO6 was predicted using LncBase Predicted v.2 and TargetScan online software, and then verifed by luciferase activity assay and RNA immunoprecipitation.
Results: UCA1 expression was higher but miR-145 expression was lower in gastric cancer cell lines or tissues, compared to the adjacent normal cell line or normal tissues. Function analysis verifed that UCA1 promoted cell proliferation and inhibited cell apoptosis in the gastric cancer cells in vitro and in vivo. Mechanistically, UCA1 could bind directly to miR-145, and MYO6 was found to be a downstream target gene of miR-145. miR-145 mimics or MYO6 siRNAs could partly reverse the efect of UCA1 on gastric cancer cells.
Conclusions: UCA1 accelerated cell proliferation and inhibited cell apoptosis through sponging miR-145 to upregulate MYO6 expression in gastric cancer, indicating that the UCA1/miR-145/MYO6 axis may serve as a potential therapeutic target for gastric cancer.
Keywords Gastric cancer, lncRNA, UCA1, miR-145, MYO6
Address and Contact Information 1 Handan Central Hospital, Handan 056001, Hebei Province, China.
2 Afliated Hospital of Hebei University of Engineering, Handan 056002, Hebei Province, China.
3 Handan First Hospital, Handan 056002, Hebei Province, China.
*Corresponding author: kongwei78@163.com
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No.  34DOI: 10.1186/s11658-021-00277-6
Authors Xianglin Hu1,2†, Zhengwang Sun1,2†, Fengfeng Li3†, Chaoyin Jiang4*, Wangjun Yan1,2* and Yangbai Sun1,2,5*
Abstract Burn injury is one of the potential causes of heterotopic ossifcation (HO), which is a rare but debilitating condition. The incidence ranges from 3.5 to 5.6 depending on body area. Burns that cover a larger percentage of the total body surface area (TBSA), require skin graft surgeries, or necessitate pulmonary intensive care are well-researched risk factors for HO. Since burns initiate such complex pathophysiological processes with a variety of molecular signal changes, it is essential to focus on HO in the specific context of burn injury to defne best practices for its treatment. There are numerous key players in the pathways of burn-induced HO, including neutrophils, monocytes, transforming growth factor-β1-expressing macrophages and the adaptive immune system. The increased infammation associated with burn injuries is also associated with pathway activation. Neurological and calcium-related contributions are also known. Endothelial-to-mesenchymal transition (EMT) and vascularization are known to play key roles in burn-induced HO, with hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) as potential initiators. Currently, non-steroidal anti-infammatory drugs (NSAIDs) and radiotherapy are efective prophylaxes for HO. Limited joint motion, ankylosis and intolerable pain caused by burn-induced HO can be efectively tackled via surgery. Efective biomarkers for monitoring burn-induced HO occurrence and bio-prophylactic and bio-therapeutic strategies should be actively developed in the future.
Keywords Burn injury, Heterotopic ossifcation, Incidence, Risk factor, Signaling pathway, Mechanism
Address and Contact Information 1 Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
3 Department of Orthopedic Surgery, The Second Afliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
4 Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
5 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
*Corresponding author: hunball2@163.com; yanwj@fudan.edu.cn; drsunyb@fudan.edu.cn
Xianglin Hu, Zhengwang Sun and Fengfeng Li contributed equally to this work
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No.  35DOI: 10.1186/s11658-021-00278-5 Volume 26 (2021) - 26:35
Authors Xiao Yang1†, Weijing Fan1†, Renyan Huang1 and Guobin Liu1,2*
Abstract Alkannin-based pharmaceutical formulations for improving wound healing have been on the market for several years. However, detailed molecular mechanisms of their action have yet to be elucidated. Here, we investigated the potential roles of AAN-II in improving the healing of pressure-induced venous ulcers using a rabbit model generated by combining deep vein thrombosis with a local skin defect/local skin defect. The extent of healing was evaluated using hematoxylin and eosin (HE) or vimentin staining. Rabbit skin fbroblasts were cultured for AAN-II treatment or TGFB1-sgRNA lentivirus transfection. ELISA was used to evaluate the levels of various cytokines, including IL-1β, IL-4, IL-6, TNF-α, VEGF, bFGF, TGF-β and PDGF. The protein levels of TGF-β sensors, including TGF-β, Smad7 and phosphor-Smad3, and total Smad3, were assayed via western blotting after TGF-β knockout or AAN-II treatment. The results show that, for this model, AAN-II facilitates ulcer healing by suppressing the development of infammation and promoting fbroblast proliferation and secretion of proangiogenic factors. AAN-II enhances the activation of the TGF-β1-Smad3 signaling pathway during skin ulcer healing. In addition, the results demonstrate that AAN-II and TGF-β have synergistic efects on ulcer healing. Our fndings indicate that AAN-II can promote healing of pressure-induced venous skin ulcers via activation of TGF-β-Smad3 signaling in fbroblast cells and provide evidence that could be used in the development of more efective treatments.
Keywords Skin ulcer, AAN-II, TGF-β1/Smad3 signaling, Infammation, Tissue repair
Address and Contact Information 1 Peripheral Vascular Disease Unit of the TCM Department, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.
2 Disease Unit of the TCM Department, Shuguang Hospital, , Shanghai University of Traditional Chinese Medicine, Zhangheng Road No. 528, Pudong New Area, 201203 Shanghai, China.
*Corresponding author: 15800885533@163.com
Xiao Yang and Weijing Fan contributed equally to this work
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No.  36DOI: 10.1186/s11658-021-00280-x Volume 26 (2021) - 26:36
Authors Jing Shao1, Yan Jin1, Chunhong Shao1, Hui Fan1, Xiaorui Wang1 and Guang Yang2*
Abstract Background: Infammatory bowel disease (IBD) is a kind of intestinal immune dysfunction disease, and its occurrence and prevalence are on the rise worldwide. As a chronic gastrointestinal disease, its pathogenesis is still unknown. Exosomes are vesicles in various body fuids that carry a variety of substances. They can mediate intercellular communication and long-distance transport of multiple media. In this study, we investigated the protein profle of serum exosomes from healthy people and IBD patients to explore a new serological biomarker for IBD.
Methods: Initially, exosomes were extracted from serum samples, and the proteins within the exosomes were identifed by label-free liquid chromatography/mass spectrometry (LC-MS/MS). Western blot and ELISA were used to assess the identifed protein. To further analyze the target protein, an acute colitis mouse model was established, and exosomes in colonic tissue and serum were extracted to investigate the protein in them.
Results: Firstly, serum exosomes were extracted from samples, and proteins in exosomes were identifed by LC-MS/MS. Through statistical analysis, we identifed 633 proteins. Among these proteins, pregnancy zone protein (PZP) showed a marked diference between patients with IBD and healthy people, in that its expression level was much higher in the IBD patients This exosomal protein was associated with immunosuppressive efects. Also, the level of PZP in colon tissue exosomes and serum exosomes of acute colitis mice was signifcantly higher than that of the control group.
Conclusions: Our fndings indicated that serum exosome PZP was present at a high level in the IBD patients. Hence it might be a promising biomarker and enhance auxiliary diagnosis of IBD.
Keywords Infammatory bowel disease, Exosome, Proteomics, Pregnancy zone protein
Address and Contact Information 1 Department of Clinical Laboratory, Shandong Provincial Hospital Afliated to Shandong First Medical University, Jinan 250021, Shandong, China.
2 Department of General Surgery, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan 250031, Shandong, China.
*Corresponding author: 710956534@qq.com
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No.  37DOI: 10.1186/s11658-021-00281-w Volume 26 (2021) - 26:37
Authors Yi Feng1,3†, Pei‐Yan He2†, Wei‐Dong Kong1,3, Wan‐Jing Cen1,3, Peng‐Lin Wang1,3, Chang Liu1,3, Wu Zhang1,3, Shu‐Shu Li1,3* and Jian‐Wei Jiang2*
Abstract Background: Iron overload can promote the development of osteoporosis by inducing apoptosis in osteoblasts. However, the mechanism by which miRNAs regulate apoptosis in osteoblasts under iron overload has not been elucidated.
Method: The miRNA expression profle in MC3T3-E1 cells under iron overload was detected by next generation sequencing. qRT-PCR was used to determine the expression of miR-3074-5p in MC3T3-E1 cells under iron overload. The proliferation of MC3T3-E1 cells was tested using CCK-8 assays, and apoptosis was measured using fow cytometry. The miRanda and TargetScan databases were used to predict the target genes of miR-3074-5p. Interaction between miR-3074-5p and the potential target gene was validated by qRT-PCR, luciferase reporter assay and western blotting.
Results: We found that iron overload decreased the cell viability and induced apoptosis of MC3T3-E1 cells. The results of next generation sequencing analysis showed that miR-3074-5p expression was signifcantly increased in MC3T3-E1 cells under iron overload conditions, which was confrmed by further experiments. The inhibition of miR-3074-5p attenuated the apoptosis of iron-overloaded MC3T3-E1 cells. Furthermore, the expression of Smad4 was decreased and was inversely correlated with miR-3074-5p expression, and overexpression of Smad4 partially reversed the viability inhibition of iron-overloaded MC3T3-E1 cells by relieving the suppression of ERK, AKT, and Stat3 phosphorylation, suggesting its regulatory role in the viability inhibition of iron-overloaded MC3T3-E1 cells. The luciferase reporter assay results showed that Smad4 was the target gene of miR-3074-5p.
Conclusion: miR-3074-5p functions as an apoptosis promoter in iron-overloaded MC3T3-E1 cells by directly targeting Smad4.
Keywords Iron overload, Osteoporosis, Apoptosis, MC3T3-E1 cells, miRNA-3074-5p
Address and Contact Information 1 Department of Orthodontics, The First Afliated Hospital of Jinan University, No.613 Huangpu Road West, Guangzhou 510630, China.
2 Department of Biochemistry, Basic Medical College, Jinan University, No.601 Huangpu Road West, Guangzhou 510632, China.
3 Department of Orthodontics, School of Stomatology, Jinan University, Guangzhou, China.
*Corresponding author: lishushu1987@126.com; jjw703@jnu.edu.cn
Yi Feng and Pei-Yan He contributed equally to this study
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No.  38DOI: 10.1186/s11658-021-00279-4 Volume 26 (2021) - 26:38
Authors Michal Arad1†, Robert A. Brown1†, Raju Khatri1, Rodney J. Taylor3,4 and Michal Zalzman1,2,3,4*
Abstract Background: Neurological disorders are considered one of the greatest burdens to global public health and a leading cause of death. Stem cell therapies hold great promise for the cure of neurological disorders, as stem cells can serve as cell replacement, while also secreting factors to enhance endogenous tissue regeneration. Adult human multipotent stem cells (MSCs) reside on blood vessels, and therefore can be found in many tissues throughout the body, including palatine tonsils. Several studies have reported the capacity of MSCs to diferentiate into, among other cell types, the neuronal lineage. However, unlike the case with embryonic stem cells, it is unclear whether MSCs can develop into mature neurons.
Methods: Human tonsillar MSCs (T-MSCs) were isolated from a small, 0.6-g sample, of tonsillar biopsies with high viability and yield as we recently reported. Then, these cells were diferentiated by a rapid, multi-stage procedure, into committed, post-mitotic, neuron-like cells using defned conditions.
Results: Here we describe for the frst time the derivation and diferentiation of tonsillar biopsy-derived MSCs (T-MSCs), by a rapid, multi-step protocol, into post-mitotic, neuron-like cells using defned conditions without genetic manipulation. We characterized our T-MSC-derived neuronal cells and demonstrate their robust diferentiation in vitro.
Conclusions: Our procedure leads to a rapid neuronal lineage commitment and loss of stemness markers, as early as three days following neurogenic diferentiation. Our studies identify biopsy-derived T-MSCs as a potential source for generating neuron-like cells which may have potential use for in vitro modeling of neurodegenerative diseases or cell replacement therapies.
Keywords Tonsil-derived multipotent stem cells (T-MSC), Biopsies, Neuron-like cells, Neuroblasts, Neuronal stem cells (NSC), Diferentiation
Address and Contact Information 1 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
2 The Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
3 Marlene and Stewart Greenbaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
4 Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
*Corresponding author: MZalzman@som.umaryland.edu
Michal Arad and Robert A. Brown contributed equally to this work
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No.  39DOI: 10.1186/s11658-021-00282-9 Volume 26 (2021) - 26:39
Authors Ghazaleh Khalili‐Tanha and Meysam Moghbeli*
Abstract Resistance against conventional chemotherapeutic agents is one of the main reasons for tumor relapse and poor clinical outcomes in cancer patients. Various mechanisms are associated with drug resistance, including drug efux, cell cycle, DNA repair and apoptosis. Doxorubicin (DOX) is a widely used frst-line anti-cancer drug that functions as a DNA topoisomerase II inhibitor. However, DOX resistance has emerged as a large hurdle in efcient tumor therapy. Furthermore, despite its wide clinical application, DOX is a double-edged sword: it can damage normal tissues and afect the quality of patients’ lives during and after treatment. It is essential to clarify the molecular basis of DOX resistance to support the development of novel therapeutic modalities with fewer and/or lower-impact side efects in cancer patients. Long non-coding RNAs (lncRNAs) have critical roles in the drug resistance of various tumors. In this review, we summarize the state of knowledge on all the lncRNAs associated with DOX resistance. The majority are involved in promoting DOX resistance. This review paves the way to introducing an lncRNA panel marker for the prediction of the DOX response and clinical outcomes for cancer patients.
Keywords Doxorubicin, Drug resistance, Cancer, Chemotherapy
Address and Contact Information Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
*Corresponding author: Meysam_moghbeli@yahoo.com; moghbelim@mums.ac.ir
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