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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Toro AU, Shukla SK, Bansal P. Emerging role of MicroRNA-Based theranostics in Hepatocellular Carcinoma. Mol Biol Rep 2023; 50:7681-7691. [PMID: 37418086 DOI: 10.1007/s11033-023-08586-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.
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Affiliation(s)
- Abdulhakim Umar Toro
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India
| | - Sudheesh K Shukla
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India.
| | - Parveen Bansal
- University Centre of Excellence in Research, Baba Farid University of Health Sciences, Faridkot, 151203, India.
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Collins KE, Wang X, Klymenko Y, Davis NB, Martinez MC, Zhang C, So K, Buechlein A, Rusch DB, Creighton CJ, Hawkins SM. Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis. Front Endocrinol (Lausanne) 2023; 14:1162786. [PMID: 37621654 PMCID: PMC10445169 DOI: 10.3389/fendo.2023.1162786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
Introduction Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.
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Affiliation(s)
- Kaitlyn E. Collins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiyin Wang
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Yuliya Klymenko
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Noah B. Davis
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Maria C. Martinez
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kaman So
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Aaron Buechlein
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Douglas B. Rusch
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Chad J. Creighton
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Shannon M. Hawkins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
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Zhou Y, Liu F, Ma C, Cheng Q. Involvement of microRNAs and their potential diagnostic, therapeutic, and prognostic role in hepatocellular carcinoma. J Clin Lab Anal 2022; 36:e24673. [PMID: 36036748 PMCID: PMC9551129 DOI: 10.1002/jcla.24673] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/01/2022] [Accepted: 08/13/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for 85%-90% of primary liver cancer. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting the 3'UTR of mRNA. Abnormal expression and regulation of miRNAs are involved in the occurrence and progression of HCC, and miRNAs can also play a role in the diagnosis and treatment of HCC as oncogenes or tumor suppressors. METHODS In the past decades, a large number of studies have shown that miRNAs play an essential regulatory role in HCC and have potential as biomarkers for HCC. We reviewed the literature to summarize these studies. RESULTS By reviewing the literature, we retrospected the roles of miRNAs in the development, diagnosis, treatment, and prognosis of HCC, and put forward prospects for the further research on miRNAs in the precision treatment of HCC. CONCLUSION MicroRNAs are important regulators and biomarkers in the occurrence, progression, outcome, and treatment of HCC, and can provide new targets and strategies for improving the therapeutic effect of HCC.
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Affiliation(s)
- Yilong Zhou
- Department of Surgery, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Fan Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Chunyang Ma
- Department of Surgery, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Qiong Cheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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Elgeshy KM, Abdel Wahab AHA. The Role, Significance, and Association of MicroRNA-10a/b in Physiology of Cancer. Microrna 2022; 11:118-138. [PMID: 35616665 DOI: 10.2174/2211536611666220523104408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/21/2022] [Accepted: 04/04/2022] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of mRNA and protein, mainly at the posttranscriptional level. Global expression profiling of miRNAs has demonstrated a broad spectrum of aberrations that correlated with several diseases, and miRNA- 10a and miRNA-10b were the first examined miRNAs to be involved in abnormal activities upon dysregulation, including many types of cancers and progressive diseases. It is expected that the same miRNAs behave inconsistently within different types of cancer. This review aims to provide a set of information about our updated understanding of miRNA-10a and miRNA-10b and their clinical significance, molecular targets, current research gaps, and possible future applications of such potent regulators.
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Affiliation(s)
- Khaled M Elgeshy
- Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
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Lee JK, Oh SJ, Gim JA, Shin OS. miR-10a, miR-30c, and miR-451a encapsulated in small extracellular vesicles are pro-senescence factors in human dermal fibroblasts. J Invest Dermatol 2022; 142:2570-2579.e6. [PMID: 35483653 DOI: 10.1016/j.jid.2022.03.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 02/23/2022] [Accepted: 03/14/2022] [Indexed: 12/01/2022]
Abstract
Although small extracellular vesicles (sEV) have been reported to play an important role in cellular senescence and aging, little is known about the potential role and function of microRNAs (miRNAs) contained within the sEV. To determine senescence-associated factors secreted from sEV of human dermal fibroblasts (HDF), we isolated and characterized sEV from non-senescent vs. senescent HDF. Small RNA sequencing analysis identified many enriched miRNAs in sEV of senescent HDF, as shown by the upregulation of miR-10a, miR-30c, and miR-451a, and downregulation of miR-128, miR-184, miR-200c, and miR-125a. Overexpression of miR-10a, miR-30c, and miR-451a induced an aging phenotype in HDF, whereas inhibition of these miRNAs reduced senescent-like phenotypes in senescent HDF. Moreover, treatment with sEV or sEV-containing conditioned medium promoted cellular senescence in HDF, whereas sEV depletion abrogated pro-senescence effects of the senescent HDF secretome. Interestingly, pro-senescence sEV miRNAs were found to have an essential role in regulating reactive oxygen species production and mitophagy activation. Taken together, our results revealed miR-10a, miR-30c, and miR-451a as pro-senescence factors that are differentially expressed in sEV of senescent HDF, demonstrating the essential role of sEV miRNAs in the biological processes of aging.
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Affiliation(s)
- Jae Kyung Lee
- BK21 Graduate program, Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Soo-Jin Oh
- BK21 Graduate program, Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Jeong-An Gim
- Medical Science Research Center, College of Medicine, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Ok Sarah Shin
- BK21 Graduate program, Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul, 08308, Republic of Korea;.
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Bao ZM, Yao D, Qian X, Zhang HG, Yang M, Guo YH, Qin L. Activating transcription factor 2 promotes the progression of hepatocellular carcinoma by inducing the activation of the WHSC1-mediated TOP2A/PI3K/AKT axis. Kaohsiung J Med Sci 2022; 38:662-674. [PMID: 35394699 DOI: 10.1002/kjm2.12536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
Activating transcription factor 2 (ATF2) is a tumor driver gene implicated in several human malignancies. This study aimed to determine the roles of ATF2 and its related molecules in the tumorigenesis of hepatocellular carcinoma (HCC). According to the Pan-cancer bioinformatics system, ATF2 is highly expressed in HCC. An increase in the expression of ATF2 was identified in clinically collected tumor tissues and procured HCC cells. The silencing of ATF2 reduced the viability, colony formation, invasion, and death resistance of HepG2 and SNU-398 cells in vitro. ATF2 promoted the transcription of Wolf-Hirschhorn syndrome candidate 1 (WHSC1) by binding to its promoter. WHSC1 further increased the expression of DNA topoisomerase II alpha (TOP2A) in HCC by inducing the dimethylation of histone H3 lysine 36 (H3K36me2) in the TOP2A promoter region. TOP2A activated the oncogenic PI3K/AKT signaling pathway. Further overexpression of WHSC1 activated the TOP2A/PI3K/AKT axis and restored the malignant behaviors of HCC cells suppressed by ATF2 silencing in vitro. In summary, this study demonstrated that, depending on WHSC1, ATF2 can activate the TOP2A/PI3K/AKT signaling cascade to promote the tumorigenesis of HCC. ATF2, WHSC1, and TOP2A may serve as potential targets in managing HCC.
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Affiliation(s)
- Zhong-Ming Bao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.,Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Dan Yao
- Department of Gastrointestinal Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Jiangsu, P. R. China
| | - Xu Qian
- Department of Thyroid and Breast Surgery, Huai'an Second People's Hospital, Jiangsu, P. R. China
| | - Hua-Guo Zhang
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Ming Yang
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Yun-Hu Guo
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
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Arechederra M, Bazai SK, Abdouni A, Sequera C, Mead TJ, Richelme S, Daian F, Audebert S, Dono R, Lozano A, Gregoire D, Hibner U, Allende DS, Apte SS, Maina F. ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma. J Hepatol 2021; 74:893-906. [PMID: 33197513 DOI: 10.1016/j.jhep.2020.11.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The tumour microenvironment shapes tumour growth through cellular communications that include both direct interactions and secreted factors. The aim of this study was to characterize the impact of the secreted glycoprotein ADAMTSL5, whose role in cancer has not been previously investigated, on hepatocellular carcinoma (HCC). METHODS ADAMTSL5 methylation status was evaluated through bisulfite sequencing, and publicly available data analysis. ADAMTSL5 RNA and protein expression were assessed in mouse models and HCC patient samples and compared to data from published datasets. Functional studies, including association of ADAMTSL5 depletion with responsiveness to clinically relevant drugs, were performed in cellular and in vivo models. Molecular alterations associated with ADAMTSL5 targeting were determined using proteomics, biochemistry, and reverse-transcription quantitative PCR. RESULTS Methylome analysis revealed hypermethylated gene body CpG islands at the ADAMTSL5 locus in both mouse and human HCC, correlating with higher ADAMTSL5 expression. ADAMTSL5 targeting interfered with tumorigenic properties of HCC cells in vitro and in vivo, whereas ADAMTSL5 overexpression conferred tumorigenicity to pre-tumoural hepatocytes sensitized to transformation by a modest level of MET receptor expression. Mechanistically, ADAMTSL5 abrogation led to a reduction of several oncogenic inputs relevant to HCC, including reduced expression and/or phosphorylation levels of receptor tyrosine kinases MET, EGFR, PDGFRβ, IGF1Rβ, or FGFR4. This phenotype was associated with significantly increased sensitivity of HCC cells to clinically relevant drugs, namely sorafenib, lenvatinib, and regorafenib. Moreover, ADAMTSL5 depletion drastically increased expression of AXL, accompanied by a sensitization to bemcentinib. CONCLUSIONS Our results point to a role for ADAMTSL5 in maintaining the function of key oncogenic signalling pathways, suggesting that it may act as a master regulator of tumorigenicity and drug resistance in HCC. LAY SUMMARY The environment of cancer cells has profound effects on establishment, progression, and response of a tumour to treatment. Herein, we show that ADAMTSL5, a protein secreted by liver cancer cells and overlooked in cancer so far, is increased in this tumour type, is necessary for tumour formation and supports drug resistance. Adamtsl5 removal conferred sensitivity of liver cancer cells to drugs used in current treatment. This suggests ADAMTSL5 as a potential marker in liver cancer as well as a possible drug target.
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Affiliation(s)
- Maria Arechederra
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Sehrish K Bazai
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Ahmed Abdouni
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Celia Sequera
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Timothy J Mead
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Sylvie Richelme
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Fabrice Daian
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Stéphane Audebert
- Aix-Marseille Univ, CRCM, Marseille Proteomics, INSERM, CNRS, Institut Paoli-Calmettes, Marseille, France
| | - Rosanna Dono
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France
| | - Anthony Lozano
- Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France
| | - Damien Gregoire
- Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France
| | - Urszula Hibner
- Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France
| | - Daniela S Allende
- Pathology Department, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Suneel S Apte
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Flavio Maina
- Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, Marseille, France.
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Sadegh Ehdaei B, Pirouzmand A, Shabani M, Mirzaei A, Moghim S. Cellular miR-101-1 Reduces Efficiently the Replication of HSV-1 in HeLa Cells. Intervirology 2021; 64:88-95. [PMID: 33626544 DOI: 10.1159/000512956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 11/10/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Herpes simplex viruses (HSVs) are widely distributed in the human population. HSV type 1 (HSV-1) is responsible for a spectrum of diseases, ranging from gingivostomatitis to keratoconjunctivitis, and encephalitis. The HSVs establish latent infections in nerve cells, and recurrences are common. Their frequent reactivation in elderly and immunosuppressed patients causes serious health complications. OBJECTIVES Due to the growing resistance to its main drug, acyclovir, alternative treatments with different mechanisms of action are required. MicroRNAs regulate host and viral gene expression posttranscriptionally. Previous studies reported that mir-101-2 expression has widely participated in the regulation of HSV-1 replication. In this study, we investigate the effect of hsa-miR-101-1 in the replication of HSV-1. METHODS We found that transfection of miR-101-1 into HeLa cells could reduce effectively HSV-1 replication using plaque assay and real-time PCR methods. RESULTS We showed that overexpression of miR-10-1 produced less viral progeny and manifested a weaker cytopathic effect, without affecting cell viability. DISCUSSION/CONCLUSION This result can give us new insights into the control of HSV-1 infections.
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Affiliation(s)
- Bahar Sadegh Ehdaei
- Department of Microbiology, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmad Pirouzmand
- Department of Microbiology, Kashan University of Medical Sciences, Kashan, Iran.,Autoimmune Diseases Research Center, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehdi Shabani
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arezoo Mirzaei
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sharareh Moghim
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran,
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Fawzy MS, Toraih EA. MicroRNA signatures as predictive biomarkers in transarterial chemoembolization‐treated hepatocellular carcinoma. PRECISION MEDICAL SCIENCES 2021. [DOI: 10.1002/prm2.12031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Manal S. Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
- Biochemistry Department, Faculty of Medicine Northern Border University Arar KSA
| | - Eman A. Toraih
- Department of Surgery Tulane University, School of Medicine New Orleans Louisiana USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Zhu M, Gong Z, Wu Q, Su Q, Yang T, Yu R, Xu R, Zhang Y. Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma. Cell Death Dis 2020; 11:632. [PMID: 32801343 PMCID: PMC7429962 DOI: 10.1038/s41419-020-02902-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 08/06/2020] [Indexed: 11/08/2022]
Abstract
Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/β-catenin-dependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4+/SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased β-catenin expression and a positive correlation between EphB4 expression and β-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of β-catenin, which triggered regulation of β-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-β-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/β-catenin-dependent manner.
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Affiliation(s)
- Man Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Zhengyan Gong
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Qing Wu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Qi Su
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Tianfeng Yang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Runze Yu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Rui Xu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China.
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13
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Abstract
Advances in molecular genetics have identified several species of RNA that fail to translate - hence the non-coding RNAs. The two major groups within this class of nucleic acids are microRNAs (miRNA) and long non-coding RNAs (lncRNA). There is growing body of evidence supporting the view that these molecules have regulatory effect on both DNA and RNA. The objective of this brief review is to explain the molecular genetic of these molecules, to summarize their potential as mediators of disease, and to highlight their value as diagnostic markers and as tools in disease management.
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Affiliation(s)
- P Waller
- Department of Biomedical Sciences, University of Kingston, London, UK
| | - A D Blann
- Institute of Biomedical Science, London, UK
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14
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Wong DKH, Cheng SCY, Mak LLY, To EWP, Lo RCL, Cheung TT, Seto WK, Fung J, Man K, Lai CL, Yuen MF. Among Patients with Undetectable Hepatitis B Surface Antigen and Hepatocellular Carcinoma, a High Proportion Has Integration of HBV DNA into Hepatocyte DNA and No Cirrhosis. Clin Gastroenterol Hepatol 2020; 18:449-456. [PMID: 31252193 DOI: 10.1016/j.cgh.2019.06.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 06/03/2019] [Accepted: 06/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In some individuals with undetectable serum levels of hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA can still be detected in serum or hepatocytes and HBV replicates at low levels-this is called occult HBV infection (OBI). OBI has been associated with increased risk of hepatocellular carcinoma (HCC). We investigated the incidence of OBI in patients with HCC and other liver diseases. We also investigated whether, in patients with OBI and HCC, HBV DNA has integrated into the DNA of hepatocytes. METHODS We collected clinical information and liver tissues from 110 HBsAg-negative patients (90 with HCC and 20 without HCC; median ages at surgical resection and biopsy collection, 64.1 and 48.6 years, respectively) who underwent liver resection or liver biopsy from November 2002 through July 2017 in Hong Kong. HBV DNA and covalently closed circular DNA (cccDNA) were analyzed and quantified by PCR in liver tissues. Integration of HBV DNA into the DNA of liver cells was detected by Alu-PCR. RESULTS Of the 90 HBsAg-negative patients with HCC, 18 had alcoholic liver disease (20%), 14 had non-alcoholic fatty liver disease or steatohepatitis (16%), 2 had primary biliary cholangitis, 2 had recurrent pyogenic cholangitis, 1 had autoimmune hepatitis, and 53 had none of these (59%). Among the 20 patients without HCC, 7 had non-alcoholic fatty liver disease or steatohepatitis, 7 had primary biliary cholangitis, and 6 had autoimmune hepatitis. OBI was detected in 62/90 patients with HCC (69%) and 3/20 patients without HCC (15%) (P < .0001). cccDNA was detectable in liver cells of 29 patients with HCC and OBI (47%) and HBV DNA had integrated into DNA of liver cells of 43 patients with HCC and OBI (69%); cccDNA and integrated HBV DNA were not detected in the 3 patients who had OBI without HCC. There were 29 patients with integration of HBV DNA among 33 patients with undetectable cccDNA in liver tissues (88%) and 14 patients with integration of HBV DNA among the 29 patients with cccDNA in liver tissues (48%) (P = .001). HBV DNA was found to integrate near genes associated with hepatocarcinogenesis, such as those encoding telomerase reverse transcriptase, lysine methyltransferase 2B, and cyclin A2. Among the 43 patients with integration of HBV DNA, 39 (91%) did not have cirrhosis. CONCLUSIONS In an analysis of clinical data and liver tissues from 90 HBsAg-negative patients with HCC, we found that almost 70% had OBI, of whom 70% had integration of HBV DNA into liver cell DNA; 90% of these patients did not have cirrhosis. HBV DNA integrated near hepatic oncogenes; these integrations might promote development of liver cancer.
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Affiliation(s)
- Danny Ka-Ho Wong
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Serene Ching Yan Cheng
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Loey Lung-Yi Mak
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Elvis Wai-Pan To
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Regina Cheuk-Lam Lo
- State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Wai-Kay Seto
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - James Fung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Kwan Man
- State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Ching-Lung Lai
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Man-Fung Yuen
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Liver Research, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
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15
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Luo L, Wang M, Li X, Tian J, Zhang K, Tan S, Luo C. Long non-coding RNA LOC285194 in cancer. Clin Chim Acta 2019; 502:1-8. [PMID: 31837299 DOI: 10.1016/j.cca.2019.12.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/27/2019] [Accepted: 12/03/2019] [Indexed: 02/07/2023]
Abstract
Long non-coding RNAs (lncRNAs) are non-protein-encoding RNAs that are usually over 200 nucleotides-long. The development of whole-genome sequencing has enabled the identification of several lncRNAs, and the determination of their critical roles in the human tumor process. LOC285194, also known as LSAMP antisense RNA 3 and tumor suppressor candidate 7 (TUSC7), is a >2-kb-long lncRNA comprised of four exons (gene ID: 285194), and located in chr3q13.31. LOC285194 expression is reported to be consistently low in tumor cells and often associated with poor clinical outcomes. Functionally, LOC285194 overexpression has been shown to inhibit cell proliferation, invasion, and migration in vitro and in vivo. Further, LOC285194 mainly suppressed or promoted the expression of related genes through direct or indirect pathways, suggesting that LOC285194 might be a feasible biomarker or therapeutic target in human cancers. Here, we reviewed and summarized existing literature on the functions and mechanisms of LOC285194 in human cancers.
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Affiliation(s)
- Lingli Luo
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Min Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Xianping Li
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Jingjing Tian
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Kan Zhang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Shan Tan
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Can Luo
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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16
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MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
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17
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Xiao J, Liu Y, Wu F, Liu R, Xie Y, Yang Q, Li Y, Liu M, Li S, Tang H. miR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells. Mol Ther 2019; 28:587-598. [PMID: 31843451 DOI: 10.1016/j.ymthe.2019.11.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 11/15/2019] [Accepted: 11/23/2019] [Indexed: 01/04/2023] Open
Abstract
Emerging evidence has indicated that abnormal methylation of DNA contributes to hepatocarcinogenesis. However, the regulatory mechanisms are not well known. Here, we revealed that microRNA-639 (miR-639) expression is downregulated in liver cancer tissues and cells. The repression of miR-639 expression was attributed to hypermethylation in its promoter region, and DNA methyltransferase (DNMT3A) was found to mediate this hypermethylation. Repression of miR-639 expression promoted cell growth and migration/invasion in vitro and the growth of tumors in xenograft mouse models. Furthermore, miR-639 bound to the 3' UTR of both MYST2 and ZEB1 and suppressed their expression. MYST2 promoted the growth of liver cancer cells and ZEB1 facilitated the migration/invasion of liver cancer cells. Ectopic expression of MYST2 and ZEB1 counteracted the repression of malignancy induced by miR-639, which coincided with the reciprocal correlation between miR-639 and MYST2 and ZEB1 expression in clinical hepatocellular carcinoma (HCC) tissues. Thus, DNMT3A-mediated hypermethylation suppressed miR-639 expression, derepressing the expression of MSYT2 and ZEB1, which promoted tumorigenesis of liver cancer. These findings may shed light on the mechanism of abnormal expression of miRNAs involved in the malignancy of liver cancer and provide new biomarkers for liver cancer.
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Affiliation(s)
- Jing Xiao
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yankun Liu
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; The Cancer Institute, Tangshan People's Hospital, Tangshan 063001, China
| | - Fuxia Wu
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Ruiyan Liu
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Laboratory Medicine, The First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Yongli Xie
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Qian Yang
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yufeng Li
- The Cancer Institute, Tangshan People's Hospital, Tangshan 063001, China
| | - Min Liu
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Shengping Li
- State Key Laboratory of Oncology in Southern China Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Hua Tang
- Tianjin Life Science Research Center, Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
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18
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Vaher H, Runnel T, Urgard E, Aab A, Carreras Badosa G, Maslovskaja J, Abram K, Raam L, Kaldvee B, Annilo T, Tkaczyk ER, Maimets T, Akdis CA, Kingo K, Rebane A. miR-10a-5p is increased in atopic dermatitis and has capacity to inhibit keratinocyte proliferation. Allergy 2019; 74:2146-2156. [PMID: 31049964 PMCID: PMC6817370 DOI: 10.1111/all.13849] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 02/27/2019] [Accepted: 03/26/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND miR-10a-5p has been shown to regulate cancer cell proliferation and invasiveness and endothelial cell inflammatory responses. The function of miR-10a-5p in the skin has not been previously studied. The aim of the current study was to examine miR-10a-5p expression, regulation, and function in keratinocytes (KCs) in association with atopic dermatitis (AD). METHODS The expression of miR-10a-5p and its target genes was analyzed using RT-qPCR, mRNA array analysis, in situ hybridization, and immunofluorescence. The transfection of miRNA mimics, cell cycle distribution analysis, and luciferase assays was used to study miR-10a-5p functions in human primary KCs. RESULTS miR-10a-5p was found to be upregulated in lesional skin from patients with AD and in proliferating KCs. Array and pathway analysis of IL-1β-stimulated KCs revealed that miR-10a-5p inhibited many genes that affect cell cycle progression and only a few inflammation-related genes. Accordingly, fewer cells in S-phase and reduced proliferation were detected as characteristics of miR-10a-5p-transfected KCs. The influence of miR-10a-5p on cell proliferation was also evident in KCs induced by AD-related cytokines, including IL-4, IL-17, and IL-1β, as measured by the capacity to strongly suppress the expression of the proliferation marker Ki-67. Among AD-related putative direct target genes, we verified hyaluronan synthase 3, a damage-associated positive regulator of KC migration and proliferation, as a direct target of miR-10a-5p. CONCLUSIONS miR-10a-5p inhibits KC proliferation and directly targets hyaluronan synthase 3 and thereby may modulate AD-associated processes in the skin.
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Affiliation(s)
- Helen Vaher
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
| | - Toomas Runnel
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
- Institute of Molecular and Cellular Biology, University of
Tartu, Tartu, Estonia
| | - Egon Urgard
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
| | - Alar Aab
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
| | - Gemma Carreras Badosa
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
| | - Julia Maslovskaja
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
| | - Kristi Abram
- Department of Dermatology and Venereology, University of
Tartu, Dermatology Clinic, Tartu University Hospital, Tartu, Estonia
| | - Liisi Raam
- Department of Dermatology and Venereology, University of
Tartu, Dermatology Clinic, Tartu University Hospital, Tartu, Estonia
| | - Bret Kaldvee
- Department of Dermatology and Venereology, University of
Tartu, Dermatology Clinic, Tartu University Hospital, Tartu, Estonia
| | - Tarmo Annilo
- Estonian Genome Center, Institute of Genomics, University
of Tartu, Tartu, Estonia
| | - Eric R. Tkaczyk
- Department of Veterans Affairs, Nashville TN and Vanderbilt Dermatology Translational Research Clinic, Nashville TN
| | - Toivo Maimets
- Institute of Molecular and Cellular Biology, University of
Tartu, Tartu, Estonia
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF),
University of Zürich, Davos, Switzerland
| | - Külli Kingo
- Department of Dermatology and Venereology, University of
Tartu, Dermatology Clinic, Tartu University Hospital, Tartu, Estonia
| | - Ana Rebane
- Institute of Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
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19
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Horii R, Honda M, Shirasaki T, Shimakami T, Shimizu R, Yamanaka S, Murai K, Kawaguchi K, Arai K, Yamashita T, Sakai Y, Yamashita T, Okada H, Nakamura M, Mizukoshi E, Kaneko S. MicroRNA-10a Impairs Liver Metabolism in Hepatitis C Virus-Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator-Like 1. Hepatol Commun 2019; 3:1687-1703. [PMID: 31832575 PMCID: PMC6887665 DOI: 10.1002/hep4.1431] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022] Open
Abstract
The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up‐regulated in advanced chronic hepatitis C (CHC). We found miR‐10a regulated various liver metabolism genes and was markedly up‐regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR‐10a was rhythmic and down‐regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1 (Bmal1) by directly suppressing the expression of RA receptor‐related orphan receptor alpha (RORA). Overexpression of miR‐10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator‐activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis‐related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR‐10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C‐related liver cirrhosis, liver tissue miR‐10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C‐related hepatocellular carcinoma recurrence. Conclusion: MiRNA‐10a is involved in abnormal liver metabolism in cirrhotic liver through down‐regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR‐10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.
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Affiliation(s)
- Rika Horii
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Masao Honda
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan.,Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Takayoshi Shirasaki
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Ryogo Shimizu
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Souma Yamanaka
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Kazuhisa Murai
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Kuniaki Arai
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Yoshio Sakai
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Taro Yamashita
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Hikari Okada
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Mikiko Nakamura
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Shuichi Kaneko
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
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20
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Liu Y, Wang X, Jiang X, Yan P, Zhan L, Zhu H, Wang T, Wen J. Tumor-suppressive microRNA-10a inhibits cell proliferation and metastasis by targeting Tiam1 in esophageal squamous cell carcinoma. J Cell Biochem 2019; 120:7845-7857. [PMID: 30426564 DOI: 10.1002/jcb.28059] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 10/22/2018] [Indexed: 01/24/2023]
Abstract
Aberrant microRNAs (miRNAs) expressions could contribute to the progression of numerous cancers, including esophageal squamous cell carcinoma, while miR-10a participates in multiple biological processes on cancers. However, the molecular mechanism of miR-10a in esophageal squamous cell carcinoma (ESCC) has not been investigated. Herein, miR-10a was significantly reduced in ESCC clinical tissues and ESCC cell lines (EC109 and TE-3). In addition, immunohistochemistry indicated that the expressions of α-SMA, Ki-67, and PCNA in tumor tissues were higher than that of controls. In vitro, overexpression of miR-10a dramatically suppressed cell proliferation and enhanced cell apoptosis, while the decrease of miR-10a expressed the opposite outcome. Specially, overexpression of miR-10a caused a G0/G1 peak accumulation. Moreover, miR-10a also negatively regulated ESCC cell migration and invasion. Furthermore, targetscan bioinformatics predictions and the dual-luciferase assay confirmed that Tiam1 was a direct target gene of miR-10a. The statistical analysis showed Tiam1 was negatively in correlation with miR-10a in ESCC patient samples. And silencing Tiam1 could lead to a decline on cell growth, invasion, and migration in ESCC cell lines, while it could enhance cell apoptosis and cause a G0/G1 peak accumulation. In vivo, it revealed that miR-10a notably decreased the tumor growth and metastasis in xenograft model and pulmonary metastasis model. And it showed a lower expressions of Tiam1 in the miR-10a mimics group by immunohistochemistry. Taken together the results, they indicated that miR-10a might function as a novel tumor suppressor in vitro and in vivo via targeting Tiam1, suggesting miR-10a to be a candidate biomarker for the ESCC therapy.
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Affiliation(s)
- Yatian Liu
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaojun Wang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuesong Jiang
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Pengwei Yan
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liangliang Zhan
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huanfeng Zhu
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tingting Wang
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Wen
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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21
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Erstad DJ, Tanabe KK. Prognostic and Therapeutic Implications of Microvascular Invasion in Hepatocellular Carcinoma. Ann Surg Oncol 2019; 26:1474-1493. [PMID: 30788629 DOI: 10.1245/s10434-019-07227-9] [Citation(s) in RCA: 281] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a morbid condition for which surgical and ablative therapy are the only options for cure. Nonetheless, over half of patients treated with an R0 resection will develop recurrence. Early recurrences within 2 years after resection are thought to be due to the presence of residual microscopic disease, while late recurrences > 2 years after resection are thought to be de novo metachronous HCCs arising in chronically injured liver tissue. Microvascular invasion (MVI) is defined as the presence of micrometastatic HCC emboli within the vessels of the liver, and is a critical determinant of early recurrence and survival. In this review, we summarize the pathogenesis and clinical relevance of MVI, which correlates with adverse biological features, including high grade, large tumor size, and epithelial-mesenchymal transition. Multiple classification schemas have been proposed to capture the heterogeneous features of MVI that are associated with prognosis. However, currently, MVI can only be determined based on surgical specimens, limiting its clinical applicability. Going forward, advances in axial imaging technologies, molecular characterization of biopsy tissue, and novel serum biomarkers hold promise as future methods for non-invasive MVI detection. Ultimately, MVI status may be used to help clinicians determine treatment plans, particularly with respect to surgical intervention, and to provide more accurate prognostication.
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Affiliation(s)
- Derek J Erstad
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.
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22
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Yan Y, Yan H, Wang Q, Zhang L, Liu Y, Yu H. Micro
RNA
10a induces glioma tumorigenesis by targeting myotubularin‐related protein 3 and regulating the Wnt/β‐catenin signaling pathway. FEBS J 2019; 286:2577-2592. [PMID: 30927504 DOI: 10.1111/febs.14824] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/21/2018] [Accepted: 03/27/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Yan Yan
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
| | - Hua Yan
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
| | - Qin Wang
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
| | - Le Zhang
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
| | - Ying Liu
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
| | - Haimiao Yu
- Department of Clinical Laboratory Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin Huan Hu Hospital China
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23
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Tao X, Yang X, Wu K, Yang L, Huang Y, Jin Q, Chen S. miR-629-5p promotes growth and metastasis of hepatocellular carcinoma by activating β-catenin. Exp Cell Res 2019; 380:124-130. [PMID: 30954576 DOI: 10.1016/j.yexcr.2019.03.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 12/14/2022]
Abstract
Aberrant miR-629-5p expression in several cancer types has been reported. Nonetheless, its potential effect and mechanism of action on tumor growth and metastasis in hepatocellular carcinoma (HCC) have rarely been analyzed. In this study, we found that miR-629-5p was upregulated in HCC tissue samples as compared to matched adjacent-tissue samples. Overexpression of miR-629-5p promoted the proliferation, migration, and invasiveness of human HCC cells in vitro, whereas miR-629-5p knockdown reduced these parameters. Consistently, miR-629-5p overexpression accelerated tumor growth and metastasis in a nude mouse model. Mechanistically, miR-629-5p directly targeted the 3' untranslated region (3'UTR) of the secreted frizzled-related protein 2 (SFRP2) mRNA and suppressed its expression, resulting in the activation of β-catenin. Inhibition of β-catenin abrogated miR-629-5p-induced growth and invasiveness. Collectively, these results suggest that miR-629-5p activates β-catenin signaling by downregulating SFRP2 and thus promotes the growth and metastasis of HCC. These data open up new prospects for HCC treatment.
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Affiliation(s)
- Xin Tao
- Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi, 046000, China
| | - Xiaoxia Yang
- Changzhi Medical College, Changzhi, 046000, China
| | - Kexin Wu
- Changzhi Medical College, Changzhi, 046000, China
| | - Liang Yang
- Changzhi Medical College, Changzhi, 046000, China
| | - Yufei Huang
- Changzhi Medical College, Changzhi, 046000, China
| | - Qian Jin
- Changzhi Medical College, Changzhi, 046000, China
| | - Suling Chen
- Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi, 046000, China.
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24
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Afshar E, Hashemi-Arabi M, Salami S, Peirouvi T, Pouriran R. Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts. Gene 2019; 702:46-55. [PMID: 30898700 DOI: 10.1016/j.gene.2019.02.106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/04/2019] [Accepted: 02/22/2019] [Indexed: 12/21/2022]
Abstract
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44high/CD24low phenotype, we screened the impacts of APAP (1 mM, 72 h) on the Epithelial to mesenchymal transition (EMT)-related expression of miRs. APAP significantly overexpressed hsa-miR-130a-3p, 192-5p, 214-3p, 101-3p, 30d-5p, 10a-5p, 99a-5p, 200c-3p, 143-3p, 30b-5p and let-7f-5p showed significant overexpression, but suppressed the expression of hsa-miR-7-5p, 149-3p, 215, 150-5p, 205-5p, 206, 10b-5p, 20b-5p, 145-5p, 26b-5p, 223-3p, 17-5p, 186-5p, 146a-5p and let-7c. It also altered on the expression of selected EMT-related genes, significantly upregulated the expression of KRT19, AKT2, CD24, and TIMP1; but downregulated the expression of MMP2, ALDH1, MMP9, TWIST, NOTCH1, and AKT1. Such shifts in expression profiles increased the population of the cells with CD44high/CD24high, and CD44low/CD24high phenotypes, significantly reduced the Twist protein and shifted the balance of E-cadherin and Vimentin proteins in favor of differentiation. Treated cells showed a significant reduction of in vitro migration and were significantly chemosensitized to Camptothecin. In conclusion, APAP, at a safe clinical dose, induced a set of targeted alterations in the EMT-related miRs which implicate, even in part, significant mitigation in chemoresistance and in vitro migration. Further studies should also be piloted to elucidate the most crucial miRs and to evaluate its clinical effectiveness.
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Affiliation(s)
- Elham Afshar
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Center for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, Telangana, India
| | - Masoud Hashemi-Arabi
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; International Branch, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siamak Salami
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Tahmineh Peirouvi
- Department of Histology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ramin Pouriran
- International Branch, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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25
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Li H, Zhao X, Li C, Sheng C, Bai Z. Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma. Cancer Manag Res 2019; 11:877-897. [PMID: 30697079 PMCID: PMC6340501 DOI: 10.2147/cmar.s186561] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background There is evidence that abnormal expression of lncRNAs is associated with hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC). However, the mechanisms remain not fully elucidated. The study aimed to identify novel lncRNAs and explore their underlying mechanisms based on the ceRNA hypothesis. Methods The RNA and miRNA expression profiling in 20 tumor and matched adjacent tissues from HBV–HCC patients were retrieved from the Gene Expression Omnibus database under accession numbers GSE77509 and GSE76903, respectively. Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) were identified using the EdgeR package. Protein–protein interaction (PPI) network was constructed for DEGs followed by module analysis. The ceRNA network was constructed based on interaction relationships between miRNAs and mRNAs/lncRNAs. The functions of DEGs were predicted using DAVID and BinGO databases. The prognosis values (overall survival [OS] and recurrence-free survival [RFS]) of ceRNA network genes were determined using The Cancer Genome Atlas (TCGA) data with Cox regression analysis and Kaplan–Meier method. Results The present study screened 643 DELs, 83 DEMs, and 1,187 DEGs. PPI network analysis demonstrated that CDK1 and CCNE1 were hub genes and extracted in functionally related modules. E2F2, CDK1, and CCNE1 were significantly enriched into cell cycle pathway. FAM182B-miR-125b-5p-E2F2 and LINC00346-miR-10a-5p-CDK1/CCNE1 ceRNA axes were obtained by constructing the ceRNA network. Patients with high expressions of DELs and DEGs in the above ceRNA axes had poor OS, while patients with the high expression of DEMs possessed excellent OS. CDK1 was also an RFS-related biomarker, with its high expression predicting poor RFS. The upregulation of LINC00346 and CDK1 but the downregulation of miR-10a-5p in HCC was validated in other microarray datasets and TCGA database. Conclusion The LINC00346-miR-10a-5p-CDK1 axis may be an important mechanism for HBV-related HCC, and genes in this ceRNA axis may be potential prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Hongyan Li
- Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China,
| | - Xiaonan Zhao
- Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China,
| | - Chenghua Li
- Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China,
| | - Chuanlun Sheng
- Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China,
| | - Zhenzi Bai
- Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China,
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26
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Gao L, Yang X, Zhang H, Yu M, Long J, Yang T. Inhibition of miR-10a-5p suppresses cholangiocarcinoma cell growth through downregulation of Akt pathway. Onco Targets Ther 2018; 11:6981-6994. [PMID: 30410355 PMCID: PMC6199228 DOI: 10.2147/ott.s182225] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Backgrounds Cholangiocarcinoma (CCA) is epithelial cell malignancy with very poor prognosis. A lot of patients were diagnosed at advanced stage of CCA and no risk factors were identified. There are limited treatment options available for the management of CCA patients. It is urgent to develop effective targeted therapies for the treatment of CCA. miRNAs are small noncoding RNAs that negatively regulate the target genes. In this study, we investigated the role and mechanism of miR-10a-5p in CCA. Methods Human CCA cell lines (CCLP1 and SG-231) were transfected with miR-10a-5p mimic or miR-10a-5p inhibitor. qRT-PCR was performed to detect the miR-10a-5p level. Proliferation, colony formation, and apoptosis were analyzed. Luciferase reporter assay was used to explore the targeting of miR-10a-5p on PTEN. For in vivo tumorigenesis assay, CCLP1 cells with stable knockdown of miR-10a-5p or control CCLP1 cells were injected subcutaneously into the flank of the SCID mice and animals were monitored for tumor growth. Results miR-10a-5p expression was significantly upregulated in human CCA cell lines (CCLP1 and SG-231). Inhibition of miR-10a-5p significantly suppressed the proliferation and induced apoptosis in CCLP1 and SG-231. PTEN is a direct target of miR-10a-5p in CCA cells. Conclusion Inhibition of miR-10a-5p can decrease CCA cells growth by downregulation of Akt pathway. These results indicate that miR-10a-5p may serve as a potential target for the treatment of CCA and help to develop effective therapeutic strategies.
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Affiliation(s)
- Lili Gao
- Center for Medical Research and Innovation,
| | | | | | - Minghua Yu
- Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| | - Jianting Long
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, People's Republic of China,
| | - Tao Yang
- Center for Medical Research and Innovation,
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27
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Luo L, Yu ZP, Qin H, Zhu ZX, Liao MH, Liao HT, Yuan KF, Zeng Y. Exosomal MicroRNA-10a Is Associated with Liver Regeneration in Rats through Downregulation of EphA4. Chin Med J (Engl) 2018; 131:454-460. [PMID: 29451151 PMCID: PMC5830831 DOI: 10.4103/0366-6999.225057] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background: MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration. Methods: The Sprague–Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA. Results: Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle. Conclusion: Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.
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Affiliation(s)
- Lin Luo
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ze-Ping Yu
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Han Qin
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ze-Xin Zhu
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ming-Heng Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hao-Tian Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ke-Fei Yuan
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yong Zeng
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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28
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Botti G, De Chiara A, Di Bonito M, Cerrone M, Malzone MG, Collina F, Cantile M. Noncoding RNAs within the
HOX
gene network in tumor pathogenesis and progression. J Cell Physiol 2018; 234:395-413. [DOI: 10.1002/jcp.27036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/25/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Gerardo Botti
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Anna De Chiara
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maurizio Di Bonito
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Margherita Cerrone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maria Gabriella Malzone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Francesca Collina
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Monica Cantile
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
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29
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Belvedere R, Saggese P, Pessolano E, Memoli D, Bizzarro V, Rizzo F, Parente L, Weisz A, Petrella A. miR-196a Is Able to Restore the Aggressive Phenotype of Annexin A1 Knock-Out in Pancreatic Cancer Cells by CRISPR/Cas9 Genome Editing. Int J Mol Sci 2018; 19:ijms19071967. [PMID: 29986379 PMCID: PMC6073506 DOI: 10.3390/ijms19071967] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/26/2018] [Accepted: 07/03/2018] [Indexed: 01/18/2023] Open
Abstract
Annexin A1 (ANXA1) is a Ca2+-binding protein that is involved in pancreatic cancer (PC) progression. It is able to mediate cytoskeletal organization maintaining a malignant phenotype. Our previous studies showed that ANXA1 Knock-Out (KO) MIA PaCa-2 cells partially lost their migratory and invasive capabilities and also the metastatization process appeared affected in vivo. Here, we investigated the microRNA (miRNA) profile in ANXA1 KO cells finding that the modification in miRNA expression suggests the significant involvement of ANXA1 in PC development. In this study, we focused on miR-196a which appeared down modulated in absence of ANXA1. This miRNA is a well known oncogenic factor in several tumour models and it is able to trigger the agents of the epithelial to mesenchymal transition (EMT), like ANXA1. Our results show that the reintroduction in ANXA1 KO cells of miR-196a through the mimic sequence restored the early aggressive phenotype of MIA PaCa-2. Then, ANXA1 seems to support the expression of miR-196a and its role. On the other hand, this miRNA is able to mediate cytoskeletal dynamics and other protein functions promoting PC cell migration and invasion. This work describes the correlation between ANXA1 and specific miRNA sequences, particularly miR-196a. These results could lead to further information on ANXA1 intracellular role in PC, explaining other aspects that are apart from its tumorigenic behaviour.
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Affiliation(s)
- Raffaella Belvedere
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
| | - Pasquale Saggese
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, via S. Allende, 1, 84081 Baronissi (SA), Italy.
| | - Emanuela Pessolano
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
| | - Domenico Memoli
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, via S. Allende, 1, 84081 Baronissi (SA), Italy.
| | - Valentina Bizzarro
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, via S. Allende, 1, 84081 Baronissi (SA), Italy.
| | - Luca Parente
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, via S. Allende, 1, 84081 Baronissi (SA), Italy.
| | - Antonello Petrella
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
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30
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Lu J, Tang L, Xu Y, Ge K, Huang J, Gu M, Zhong J, Huang Q. Mir-1287 suppresses the proliferation, invasion, and migration in hepatocellular carcinoma by targeting PIK3R3. J Cell Biochem 2018; 119:9229-9238. [PMID: 29953647 DOI: 10.1002/jcb.27190] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/24/2018] [Indexed: 12/22/2022]
Abstract
Mature microRNAs (miRNAs) are a class of small noncoding RNA molecules involved in regulation of post-translational gene expression. Although aberrant levels of miRNAs have been found in various tumor tissues, their importance in tumor development and the molecular basis of their regulatory role remain unclear. Our bioinformatic analysis on The Cancer Genome Atlas database and microarray-based comparison of miRNA in different cell lines revealed that the level of mir-1287 is suppressed in hepatocellular carcinoma (HCC) cells. When upregulated, mir-1287 can reduce the tumorigenesis phenotypes of HCC cells in several in vitro models. We further found that mir-1287 directly targets messenger RNA encoding PIK3R3, which is a tumor-promoting factor acting in several pathways linked to tumorigenesis. Our study suggests that aberrant suppression of mir-1287 is potentially responsible for the development of HCC, and miRNA-based strategies may be developed for efficient detection and treatment of HCC.
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Affiliation(s)
- Junhao Lu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Licheng Tang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuqiang Xu
- Shanghai High-Tech United Bio-Technological R&D Co, Ltd, Shanghai, China
| | - Kuikui Ge
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jinjiang Huang
- Shanghai High-Tech United Bio-Technological R&D Co, Ltd, Shanghai, China
| | - Meigang Gu
- Laboratory of Virology and Infectious Disease Center for the Study of Hepatitis C, Rockefeller University, New York, New York
| | - Jiang Zhong
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Qingshan Huang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.,Shanghai High-Tech United Bio-Technological R&D Co, Ltd, Shanghai, China
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31
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Xu C, Zhang H, Gu W, Wu H, Chen Y, Zhou W, Sun B, Shen X, Zhang Z, Wang Y, Liu Y, Yuan W. The microRNA-10a/ID3/RUNX2 axis modulates the development of Ossification of Posterior Longitudinal Ligament. Sci Rep 2018; 8:9225. [PMID: 29907859 PMCID: PMC6003989 DOI: 10.1038/s41598-018-27514-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 05/31/2018] [Indexed: 01/07/2023] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) presents as pathological heterotopic ossification of the spinal ligaments. However, its underlying molecular mechanism is still unclear. Our previous findings suggested that altered microRNA regulatory network are critical for the development of OPLL. Here, we set out to unveiling the detailed mechanism of those altered OPLL-specific microRNAs. We screened a set of differentially expressed OPLL-specific microRNAs from the previous sequencing data and showed that microRNA-10a actively modulates the ossification of posterior ligament cells in vitro. Using a tissue-engineered scaffold grown from 4-week-old BALB/c homozygous nude mice, we found that altered microRNA-10a expression in posterior ligament cells indeed affected the heterotopic bone formation in vivo. Furthermore, computational analysis showed that the negative ossification regulator ID3 is a functional target gene of microRNA-10a, and its expression was also significantly altered during microRNA-10a modulation both in vitro and in vivo. Also, we have demonstrated that the ossification promoting function of microRNA-10a requires ID3, as ID3 actively inhibits RUNX2. Thus, we identified a critical role for highly altered OPLL-specific microRNA-10a in regulating the development of OPLL by modulating the ID3/RUNX2 axis.
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Affiliation(s)
- Chen Xu
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Hao Zhang
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Wei Gu
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Huiqiao Wu
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Yuanyuan Chen
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China.,Department of Orthopedic Surgery, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 800th Yi Shan Road, Shanghai, 200233, P.R. China
| | - Wenchao Zhou
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Baifeng Sun
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Xiaolong Shen
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China
| | - Zicheng Zhang
- Administration Office for Graduate Students, Changhai Hospital, Second Military Medical University, 168th Chang Hai Road, Shanghai, 200433, P.R. China
| | - Yue Wang
- Research Center of Developmental Biology, Second Military Medical University, 800th Xiang Yin Road, Shanghai, 200433, P.R. China.
| | - Yang Liu
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China.
| | - Wen Yuan
- Spine Center, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, P.R. China.
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Fang F, Song T, Zhang T, Cui Y, Zhang G, Xiong Q. MiR-425-5p promotes invasion and metastasis of hepatocellular carcinoma cells through SCAI-mediated dysregulation of multiple signaling pathways. Oncotarget 2018; 8:31745-31757. [PMID: 28423650 PMCID: PMC5458244 DOI: 10.18632/oncotarget.15958] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/13/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) play critical roles in hepatocellular carcinoma (HCC) progression and are key determinants of prognosis. In this study, we found that miR-425-5p was elevated in HCC and correlated with poor prognostic clinicopathological features and low post-operative long-term survival. Multivariate survival analysis indicated that miR-425-5p expression was an independent risk factor for overall and disease-free survival. Interestingly, miR-425-5p promoted invasion and metastasis by HCC cells, but not HCC cell proliferation or apoptosis in vitro. SCAI and PTEN were determined to be downstream targets of miR-425-5p. miR-425-5p-mediated effects were inhibited by ectopic expression of SCAI, and PTEN exhibited a smaller inhibitory effect. SCAI also suppressed PTEN expression. In addition, miR-425-5p promoted epithelial-to-mesenchymal transition (EMT), which was antagonized by SCAI. miR-425-5p also promoted HCC cell invasion and metastasis via SCAI-mediated dysregulation of integrin β1-Fak/Src-RhoA/CDC42, PTEN-AKT, and TIMP2-MMP2/MMP9 signaling. Finally, miR-425-5p promoted metastasis in a xenograft mouse model of HCC. These results indicate that miR-425-5p facilitates EMT and extracellular matrix degradation and promotes HCC metastasis through SCAI-mediated dysregulation of multiple signaling pathways. MiR-425-5p is therefore a potential prognostic biomarker and novel therapeutic target in HCC.
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Affiliation(s)
- Feng Fang
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China
| | - Tianqiang Song
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China
| | - Ti Zhang
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China
| | - Yunlong Cui
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China
| | - Gewen Zhang
- Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Qingqing Xiong
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China
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33
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Kang S, Zhao Y, Liu J, Wang L, Zhao G, Chen X, Yao A, Zhang L, Zhang X, Li X. Association of Vitamin D receptor Fok I polymorphism with the risk of prostate cancer: a meta-analysis. Oncotarget 2018; 7:77878-77889. [PMID: 27788484 PMCID: PMC5363628 DOI: 10.18632/oncotarget.12837] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 10/13/2016] [Indexed: 11/25/2022] Open
Abstract
Several previous studies have been reported to examine the association between Vitamin D receptor (VDR) gene Fok I polymorphism and susceptibility to prostate cancer (PCa), however the results remain inconclusive. To provide a relatively comprehensive account of the association, we searched PubMed, Embase, CNKI, and Wanfang for eligible studies and carry out this meta-analysis. A total of 27 case-control studies with 10,486 cases and 10,400 controls were included. In the overall analysis, Fok I polymorphism was not significantly associated with the susceptibility to PCa. Subgroup analyses showed that significantly association was existed in Caucasian population, the subgroup of population-based controls and the stratified group with advanced tumor.These results indicate that the VDR Fok I polymorphism might be capable of causing PCa susceptibility and could be a promising target to forecast the PCa risk for clinical practice. However further well-designed epidemiologic studies are needed to confirm this conclusion.
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Affiliation(s)
- Shaosan Kang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Yansheng Zhao
- Department of Imaging, KaiLuan General Hosptial, Tangshan 063000, China
| | - Jian Liu
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Lei Wang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Geng Zhao
- Department of Urology, KaiLuan General Hospital, Tangshan 063000, China
| | - Xi Chen
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Anliang Yao
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Liguo Zhang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Xiaojun Zhang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
| | - Xiaoqiang Li
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, China
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Hu Y, Guo X, Wang J, Liu Y, Gao H, Fan H, Nong X, Yang X, Liu M, Li S, Tang H. A novel microRNA identified in hepatocellular carcinomas is responsive to LEF1 and facilitates proliferation and epithelial-mesenchymal transition via targeting of NFIX. Oncogenesis 2018; 7:22. [PMID: 29472529 PMCID: PMC5833431 DOI: 10.1038/s41389-017-0010-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 10/27/2017] [Accepted: 11/08/2017] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers. It has been demonstrated that various cellular microRNAs (miRNAs) play an important role in HCC development. Here, we analyzed the miRNA profile in HCC tissues by Solexa sequencing, and we identified a novel microRNA, miR-HCC1, which is upregulated in HCC tissues. Further experiments showed that miR-HCC1 promoted HCC cell proliferation in vivo and in vitro, and migration and invasion resulting from the epithelial-mesenchymal transition (EMT) process. Nuclear factor I/X (NFIX), which inhibited cell proliferation, migration and invasion in HCC cells, was identified as a direct and functional target of miR-HCC1. Furthermore, lymphoid enhancer binding factor 1 (LEF1), a transcription factor, was shown to bind the promoter of miR-HCC1 and activate its expression. Collectively, these results indicate that LEF1-upregulated miR-HCC1 functions as an oncogene through the negative regulation of NFIX expression, which links the LEF1/miR-HCC1/NFIX axis to contribute to cell proliferation, migration and invasion of HCC cells and could provide novel insights into miRNA function and hepatocarcinogenesis and potential biomarkers for HCC.
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Affiliation(s)
- Yaqi Hu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Xu Guo
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Jinxia Wang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Yankun Liu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.,The Cancer Institute, Tangshan People's Hospital, 063001, Tangshan, China
| | - Huijie Gao
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Hongxia Fan
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | | | | | | | - Shengping Li
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, 510060, Guangzhou, China
| | - Hua Tang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
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Abstract
Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
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Affiliation(s)
- Zhenfang Du
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Christine M Lovly
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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36
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Zhang Q, Song G, Yao L, Liu Y, Liu M, Li S, Tang H. miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:14. [PMID: 29378599 PMCID: PMC5789631 DOI: 10.1186/s13046-018-0681-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 01/15/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) plays a critical role in the tumorigenic behavior of human hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to participate in HCC development via the regulation of their target genes. However, HBV-modulated miRNAs involved in tumorigenesis remain to be identified. Here, we found that a novel highly expressed miRNA, TLRC-m0008_3p (miR-3928v), may be an important factor that promotes the malignancy of HBV-related HCC. METHODS Solexa sequencing was applied to profile miRNAs, and RT-qPCR was used to identify and quantitate miRNAs. We studied miR-3928v function in HCC cell lines by MTT, colony formation, migration/invasion, and vascular mimicry (VM) assays in vitro and by a xenograft tumor model in vivo. Finally, we predicted and verified the target gene of miR-3928v by a reporter assay, studied the function of this target gene, and cloned the promoter of miR-3928v and the transcription factor for use in dual-luciferase reporter assays and EMSAs. RESULTS A variant of miR-3928 (miR-3928v) was identified and found to be highly expressed in HBV (+) HCC tissues. Voltage-dependent anion channel 3 (VDAC3) was validated as a target of miR-3928v and found to mediate the effects of miR-3928v in promoting HCC growth and migration/invasion. Furthermore, HBx protein increased early growth response 1 (EGR1) expression and facilitated its translocation into the nucleus to enhance miR-3928v promoter activity in an NF-κB signaling-dependent manner. CONCLUSIONS miR-3928v is induced by HBx through the NF-κB/EGR1 signaling pathway and down-regulates the tumor suppressor gene VDAC3 to accelerate the progression of HCC.
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Affiliation(s)
- Qiaoge Zhang
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China
| | - Ge Song
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China
| | - Lili Yao
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China
| | - Yankun Liu
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China ,grid.459483.7The Cancer Institute, Tangshan People’s Hospital, Tangshan, 063001 China
| | - Min Liu
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China
| | - Shengping Li
- 0000 0001 2360 039Xgrid.12981.33Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, 510060 China
| | - Hua Tang
- 0000 0000 9792 1228grid.265021.2Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070 China
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37
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MiR-770 inhibits tumorigenesis and EMT by targeting JMJD6 and regulating WNT/β-catenin pathway in non-small cell lung cancer. Life Sci 2017; 188:163-171. [DOI: 10.1016/j.lfs.2017.09.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 08/31/2017] [Accepted: 09/01/2017] [Indexed: 11/22/2022]
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38
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Hua KT, Hong JB, Sheen YS, Huang HY, Huang YL, Chen JS, Liao YH. miR-519d Promotes Melanoma Progression by Downregulating EphA4. Cancer Res 2017; 78:216-229. [PMID: 29093007 DOI: 10.1158/0008-5472.can-17-1933] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/08/2017] [Accepted: 10/27/2017] [Indexed: 12/11/2022]
Abstract
Increasing evidence suggests that there is a unique cell subpopulation in melanoma that can form nonadherent melanospheres in serum-free stem cell medium, mimicking aggressive malignancy. Using melanospheres as a model to investigate progression mechanisms, we found that miR-519d overexpression was sufficient to promote cell proliferation, migration, invasion, and adhesion in vitro and lung metastatic capability in vivo The cell adhesion receptor EphA4 was determined to be a direct target of miR-519d. Forced expression of EphA4 reversed the effects of miR-519d overexpression, whereas silencing of EphA4 phenocopied the effect of miR-519d. Malignant progression phenotypes were also affected at the level of epithelial-to-mesenchymal transition and the ERK1/2 signaling pathway inversely affected by miR-519d or EphA4 expression. In clinical specimens of metastatic melanoma, we observed significant upregulation of miR-519d and downregulation of EphA4, in the latter case correlated inversely with overall survival. Taken together, our results suggest a significant functional role for miR-519d in determining EphA4 expression and melanoma progression.Significance: These results suggest a significant role for miR-519d in determining expression of a pivotal cell adhesion molecule that may impact risks of malignant progression in many cancers. Cancer Res; 78(1); 216-29. ©2017 AACR.
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Affiliation(s)
- Kuo-Tai Hua
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Bong Hong
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Shuan Sheen
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsin-Yi Huang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Ling Huang
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jau-Shiuh Chen
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Hua Liao
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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Shu J, Silva BVRE, Gao T, Xu Z, Cui J. Dynamic and Modularized MicroRNA Regulation and Its Implication in Human Cancers. Sci Rep 2017; 7:13356. [PMID: 29042600 PMCID: PMC5645395 DOI: 10.1038/s41598-017-13470-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 09/26/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNA is responsible for the fine-tuning of fundamental cellular activities and human disease development. The altered availability of microRNAs, target mRNAs, and other types of endogenous RNAs competing for microRNA interactions reflects the dynamic and conditional property of microRNA-mediated gene regulation that remains under-investigated. Here we propose a new integrative method to study this dynamic process by considering both competing and cooperative mechanisms and identifying functional modules where different microRNAs co-regulate the same functional process. Specifically, a new pipeline was built based on a meta-Lasso regression model and the proof-of-concept study was performed using a large-scale genomic dataset from ~4,200 patients with 9 cancer types. In the analysis, 10,726 microRNA-mRNA interactions were identified to be associated with a specific stage and/or type of cancer, which demonstrated the dynamic and conditional miRNA regulation during cancer progression. On the other hands, we detected 4,134 regulatory modules that exhibit high fidelity of microRNA function through selective microRNA-mRNA binding and modulation. For example, miR-18a-3p, -320a, -193b-3p, and -92b-3p co-regulate the glycolysis/gluconeogenesis and focal adhesion in cancers of kidney, liver, lung, and uterus. Furthermore, several new insights into dynamic microRNA regulation in cancers have been discovered in this study.
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Affiliation(s)
- Jiang Shu
- Systems Biology and Biomedical Informatics (SBBI) Laboratory, Department of Computer Science and Engineering, Lincoln, NE, 68588, USA
| | - Bruno Vieira Resende E Silva
- Systems Biology and Biomedical Informatics (SBBI) Laboratory, Department of Computer Science and Engineering, Lincoln, NE, 68588, USA
| | - Tian Gao
- Systems Biology and Biomedical Informatics (SBBI) Laboratory, Department of Computer Science and Engineering, Lincoln, NE, 68588, USA
| | - Zheng Xu
- Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
- Quantitative Life Sciences Initiative, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Juan Cui
- Systems Biology and Biomedical Informatics (SBBI) Laboratory, Department of Computer Science and Engineering, Lincoln, NE, 68588, USA.
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40
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The construction of intrahepatic cholangiocarcinoma model in zebrafish. Sci Rep 2017; 7:13419. [PMID: 29042681 PMCID: PMC5645375 DOI: 10.1038/s41598-017-13815-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 10/02/2017] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor, difficult to diagnose even at an early stage. In this study, we successfully constructed an nras61K-induced ICC model in zebrafish. Transcriptome analysis and gene set enrichment analysis (GSEA) of liver samples of the ICC and WT (wild-type) zebrafish revealed that the genes differentially expressed between the two groups were mainly involved in focal adhesion, chemokine signaling and metabolic pathways. Analysis of DNA methylomes revealed that compared with WT samples, methylated genes in ICC samples were enriched in functions associated with cellular, single-organism and metabolic processes. In particular, our result discovered eleven potential biomarker genes of ICC which were conserved between zebrafish and humans. Moreover, three potential biomarker genes were hypomethylated in the tumorigenesis of ICC: ehf, epha4 and itgb6. In summary, our study provides a comprehensive analysis of molecular mechanisms accompanying the progressive nras61K-induced ICC. This work indicates that our transgenic zebrafish could be a valuable model, not only for studying liver cancer, but also for exploring new therapeutic targets.
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41
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KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells. Oncotarget 2017; 8:17712-17725. [PMID: 27487123 PMCID: PMC5392280 DOI: 10.18632/oncotarget.10832] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 06/17/2016] [Indexed: 11/25/2022] Open
Abstract
Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to hepatocellular carcinoma (HCC) tumorigenesis and development. Here, we found that miR-615-5p was obviously downregulated in HCC. Furthermore, the deficiency of demethylase KDM4B stimulated the CpG methylation of miR-615-5p promoter and then decreased the miR-615-5p expression. The Ras-related protein RAB24 was found to be downregulated by miR-615-5p. The low level of miR-615-5p increased the expression of RAB24 and facilitated HCC growth and metastasis in vitro and in vivo. Moreover, miR-615-5p suppresses HCC cell growth by influencing cell cycle progression and apoptosis. Downregulation of miR-615-5p and upregulation of RAB24 promotes the epithelial-mesenchymal transition (EMT), adhesion and vasculogenic mimicry (VM) of HCC cells, all of which contribute to cell motility and metastasis. Thus, miR-615-5p, who is downregulated by KDM4B-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting RAB24 expression in HCC. In conclusion, our findings characterize miR-615-5p as an important epigenetically silenced miRNA involved in the Rab-Ras pathway in hepatocellular carcinoma and expand our understanding of the molecular mechanism underlying hepatocarcinogenesis and metastasis.
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42
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Zhan Y, Zheng N, Teng F, Bao L, Liu F, Zhang M, Guo M, Guo W, Ding G, Wang Q. MiR-199a/b-5p inhibits hepatocellular carcinoma progression by post-transcriptionally suppressing ROCK1. Oncotarget 2017; 8:67169-67180. [PMID: 28978024 PMCID: PMC5620164 DOI: 10.18632/oncotarget.18052] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 04/26/2017] [Indexed: 01/18/2023] Open
Abstract
In this study, we explored the actions of miR-199a/b-5p during hepatocellular carcinoma (HCC) progression and its potential target genes. Through heatmap miRNA expression analysis of 15 matched HCC tumor and adjacent non-tumor liver tissues from the TCGA database, we detected 19 mRNAs that were upregulated and 13 that were downregulated specifically in HCC. Among these, miR-199 family members were downregulated in HCC tumors and cell lines, as compared to controls. Low miR-199a/b-5p expression was also associated with poor overall survival of HCC patients. miR-199a/b-5p overexpression in HCC cell lines inhibited cell proliferation, migration and invasion, both in vitro and in vivo. In addition, miR199-a/b-5p post-transcriptionally suppressed Rho-associated coiled-coil kinase 1 (ROCK1). This in turn led to inhibition of ROCK1/MLC and PI3K/Akt signaling, which is necessary for HCC proliferation and metastasis. These results indicate that miR-199a/b acts as tumor suppressors in HCC and represent promising therapeutic targets.
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Affiliation(s)
- Yangyang Zhan
- Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China
| | - NanXin Zheng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Leilei Bao
- Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China.,Department of Pharmacy, No. 411 Hospital of PLA, Shanghai 200080, China
| | - Fang Liu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Mingjian Zhang
- Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China
| | - Meng Guo
- Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China.,Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Wenyuan Guo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Guoshan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Quanxing Wang
- Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China
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43
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Gao W, Sun W, Yin J, Lv X, Bao J, Yu J, Wang L, Jin C, Hu L. Screening candidate microRNAs (miRNAs) in different lambskin hair follicles in Hu sheep. PLoS One 2017; 12:e0176532. [PMID: 28464030 PMCID: PMC5413071 DOI: 10.1371/journal.pone.0176532] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 04/12/2017] [Indexed: 12/31/2022] Open
Abstract
Hu sheep lambskin is a unique white lambskin from China that exhibits three types of flower patterns, including small waves, medium waves, and large waves, with small waves considered the best quality. However, our understanding of the molecular mechanism underlying flower pattern formation in Hu sheep lambskin is limited. The aim of the present study was to further explore the relevance between candidate microRNAs (miRNAs) and developmental characteristics of hair follicles and screen miRNAs for later functional validation. Herein, we employed Illumina Hiseq 2500 to identify differentially expressed miRNAs in hair follicles of different flower patterns with small, medium, and large waves to construct a comprehensive sequence database on the mechanism of hair follicle development. Paraffin sections of lambskin tissue were prepared to assess the structure of different hair follicles. Expression levels of candidate miRNAs in different flower patterns were analyzed by relative quantitation using real-time PCR, combined with histological observation and micro-observation technologies, and the correlation between expression levels of candidate miRNAs and histological properties of hair follicles was analyzed by using SPSS 17.0. A total of 522 differentially expressed miRNAs were identified, and RNA-seq analysis detected 7,266 target genes in different groups of flower patterns. Gene ontological analysis indicated these target genes were mainly involved in cell proliferation, differentiation, growth, apoptosis, and ion transport, and 14 miRNAs, including miR-143, miR-10a, and let-7 were screened as candidate miRNAs in Hu sheep hair follicle growth and development. In the same field of vision, variance analysis showed that the number of secondary follicles in small waves was significantly larger than that in large and medium waves (P<0.01); the diameter of the primary and secondary follicles in large waves was respectively larger than those in medium and small waves (P<0.01). Combined with correlation analysis between miRNA expression and histological properties of hair follicles, highly significant differences in miRNA-143 expression levels between large and small waves were observed (P<0.01), and significant differences in the miRNA-10a expression levels between large and small waves (P<0.05) and in let-7i expression levels between large and medium waves were observed (P<0.05). Significant differences in the expression of novel miRNAs of NW_004080184.1_6326 between medium and large waves were detected (P<0.05), and highly significant differences between medium and small waves were observed (P<0.01). Highly significant differences in the expression level of NW_004080165.1_8572 between medium and large and small waves (P<0.01), in that of NW_004080181.1_3961 between medium and small waves (P<0.01), and in that of NW_004080190.1_13733 between medium and large waves were observed, whereas no significant differences in the other miRNAs among large, medium, and small waves were detected. Overall, the present study showed that miRNA-143, miRNA-10a, let-7i, NW_004080184.1_6326, NW_004080165.1_8572, NW_004080181.1_3961, and NW_004080190.1_13733 could be considered as important candidate genes, indicating these seven miRNAs may play significant roles in hair follicle growth and development in Hu sheep lambskin.
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Affiliation(s)
- Wen Gao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Wei Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
- * E-mail:
| | - Jinfeng Yin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xiaoyang Lv
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jianjun Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jiarui Yu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Lihong Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Chengyan Jin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Liang Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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44
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miR-10a suppresses colorectal cancer metastasis by modulating the epithelial-to-mesenchymal transition and anoikis. Cell Death Dis 2017; 8:e2739. [PMID: 28383561 PMCID: PMC5477594 DOI: 10.1038/cddis.2017.61] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 12/28/2016] [Accepted: 01/03/2017] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) have a critical role in tumorigenesis and metastasis, which are major obstacles of cancer therapy. However, the role of miRNAs in colorectal cancer (CRC) metastasis remains poorly understood. Here, we found that miRNA-10a (miR-10a) was upregulated in primary CRC tissues and cell line (SW480) derived from primary CRC compared with metastatic cancer tissues in lymph node and cell line (SW620). The differential expression of miR-10a was inversely correlated with distant metastasis and invasion depth. miR-10a promoted migration and invasion in vitro but inhibited metastasis in vivo by regulating the epithelial-to-mesenchymal transition and anoikis. Furthermore, matrix metalloproteinase 14 (MMP14) and actin gamma 1 (ACTG1) were validated as target genes of miR-10a in CRC cells. Ectopic expression of MMP14 and ACTG1 counteracted the decreased cell adhesion and anoikis resistance activities induced by miR-10a. These findings not only describe the mechanism by which miR-10a suppresses CRC metastasis but also suggest the potential prognostic and therapeutic value of miR-10a in CRC patients.
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45
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XRN2 promotes EMT and metastasis through regulating maturation of miR-10a. Oncogene 2017; 36:3925-3933. [PMID: 28319071 DOI: 10.1038/onc.2017.39] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 01/05/2017] [Accepted: 01/31/2017] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) have been proposed as critical regulatory molecules in the epithelial-mesenchymal transition (EMT) program. However, the roles of mature miRNA biogenesis during EMT process needs to be defined. Here we determined that increased expression of XRN2 induced EMT and promoted metastasis in vitro and in vivo. Furthermore, we uncovered that XRN2 functions as pro-metastatic gene, which accelerates miR-10a maturation by binding pre-miR-10a in a DICER-independent manner. These findings suggest that XRN2 is a novel regulator of EMT that contributes to the metastatic processes in lung cancer through a novel miRNA regulatory mechanism.
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Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development. Hepatol Res 2017; 47:80-94. [PMID: 27138942 DOI: 10.1111/hepr.12737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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47
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Chang RM, Xiao S, Lei X, Yang H, Fang F, Yang LY. miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma. Clin Cancer Res 2016; 23:2593-2604. [PMID: 27827315 DOI: 10.1158/1078-0432.ccr-16-0851] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 10/13/2016] [Accepted: 10/20/2016] [Indexed: 11/16/2022]
Abstract
Purpose: Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms.Experimental Design: 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both in vivo and in vitro The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry.Results: Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models.Conclusions: Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. Clin Cancer Res; 23(10); 2593-604. ©2016 AACR.
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Affiliation(s)
- Rui-Min Chang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuai Xiao
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiong Lei
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Yang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Feng Fang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lian-Yue Yang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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48
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Fan Q, Meng X, Liang H, Zhang H, Liu X, Li L, Li W, Sun W, Zhang H, Zen K, Zhang CY, Zhou Z, Chen X, Ba Y. miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma. Protein Cell 2016; 7:899-912. [PMID: 27815824 PMCID: PMC5205661 DOI: 10.1007/s13238-016-0316-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 08/06/2016] [Indexed: 12/21/2022] Open
Abstract
The BCL6 (B-Cell Lymphoma 6) gene is a proto-oncogene that is often expressed in diffuse large B-cell lymphomas (DLBCLs). BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3′-untranslated region (3′-UTR) of BCL6. We further identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experimentally validated that miR-10a directly recognizes the 3′-UTR of the BCL6 transcript and regulated BCL6 expression. Furthermore, we demonstrated that negatively regulating BCL6 by miR-10a suppressed the proliferation and promoted apoptosis of DLBCL cells.
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Affiliation(s)
- Qian Fan
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Xiangrui Meng
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Hongwei Liang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Huilai Zhang
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Xianming Liu
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Lanfang Li
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Wei Li
- Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Wu Sun
- Department of Digestion, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Haiyang Zhang
- Department of Digestion, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Chen-Yu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Zhen Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
| | - Xi Chen
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
| | - Yi Ba
- Department of Digestion, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
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de Marcondes PG, Morgado-Díaz JA. The Role of EphA4 Signaling in Radiation-Induced EMT-Like Phenotype in Colorectal Cancer Cells. J Cell Biochem 2016; 118:442-445. [PMID: 27632701 DOI: 10.1002/jcb.25738] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 09/13/2016] [Indexed: 12/14/2022]
Abstract
Radiotherapy is widely used for advanced rectal tumors. However, refractory metastasis has become the major cause of therapy failure in rectal cancer patients. Understanding the molecular mechanism that controls the aggressive cellular response to this treatment is essential for developing new therapeutic applications and improving radiotherapy response in colorectal cancer patients. Using the progeny of cells that were submitted to irradiation, we have demonstrated that the PI3K/AKT, Wnt/β-catenin signaling pathways as well as ERK1/2 downstream of EPHA4 receptor activation, play an important role in the regulation of events related with the EMT development, which may be associated with the therapeutic failure in rectal cancer after radiotherapy. Here, we further discuss about EphA4 receptor as a potential therapeutic target for the treatment of this cancer type. J. Cell. Biochem. 118: 442-445, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Priscila Guimarães de Marcondes
- Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ 20230-051, Brazil
| | - José Andrés Morgado-Díaz
- Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ 20230-051, Brazil
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50
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Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival. Blood 2016; 128:1578-89. [PMID: 27338098 DOI: 10.1182/blood-2016-02-702530] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/15/2016] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV(+) PTLD and DLBCL.
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