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Maiyulan A, Matsumoto Y, Wang H, Murakami K, Toyozumi T, Otsuka R, Shiraishi T, Kinoshita K, Hu J, Iida S, Morishita H, Makiyama T, Nishioka Y, Kano M, Matsubara H. Hypoxia‑regulated exosomal miR‑185 inhibits esophageal squamous cell carcinoma progression and predicts prognosis. Oncol Lett 2024; 28:334. [PMID: 38827568 PMCID: PMC11140231 DOI: 10.3892/ol.2024.14467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 04/18/2024] [Indexed: 06/04/2024] Open
Abstract
Despite advances in treatment and diagnosis, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains poor. MicroRNAs (miRNAs/miRs) are associated with prognosis in esophageal cancer, indicating that they may help guide treatment decisions. The aim of the present study was to explore exosomal miR-185 as a candidate prognostic biomarker and therapeutic target in ESCC, to investigate its biological function and clinical significance, and to ascertain the applicability of circulating exosomal miR-185 for the development of targeted drugs for ESCC treatment. A GeneChip miRNA array was used to compare exosomal miRNA expression in ESCC cell lines under hypoxia with those under normoxia. Exosomal miR-185 expression was then confirmed by reverse transcription-quantitative PCR. Patient background and prognosis were compared between high and low miR-185 expression groups. Functional analyses were performed to evaluate the antitumor effects of miR-185 in ESCC cells. Global Gene Set Enrichment Analysis of The Cancer Genome Atlas data was also performed, and differentially expressed exosomal miRNAs under hypoxia were identified compared to those under normoxia. Hypoxia markedly decreased the expression of exosomal miR-185 in KYSE-960 and T.Tn cell culture media. Overexpression of miR-185 suppressed the migration, invasion and colony-forming abilities of ESCC lines, and also suppressed cell cycle progression and promoted apoptosis after cisplatin treatment. Notably, high miR-185 expression was associated with signaling pathways related to cell death, DNA damage and p53. Furthermore, circulating exosomal miR-185 levels were associated with cN and cStage, and could predict progression-free survival and disease-specific survival of patients with ESCC after initial treatment. In conclusion, miR-185 holds potential as a prognostic biomarker and therapeutic target in ESCC.
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Affiliation(s)
- Abula Maiyulan
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Huan Wang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Ryota Otsuka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tadashi Shiraishi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kazuya Kinoshita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Jie Hu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shinichiro Iida
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroki Morishita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tenshi Makiyama
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yuri Nishioka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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Alfaifi J. miRNAs Role in Wilms tumor pathogenesis: Signaling pathways interplay. Pathol Res Pract 2024; 256:155254. [PMID: 38460245 DOI: 10.1016/j.prp.2024.155254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Wilms' tumors (WTs) are the most common type of kidney tumor in children, and a negative outlook is generally associated with widespread anaplastic. MicroRNAs (miRNAs) are crucial in the development of WT by regulating the expression of specific genes. There is an increasing amount of research that connects the dysregulation of miRNAs to the development of various renal illnesses. The conditions encompassed are renal fibrosis, renal cancers, and chronic and polycystic kidney disease. Dysregulation of several important miRNAs, either oncogenic or tumor-suppressing, has been found in WT. The present state of knowledge on the involvement of dysregulated miRNAs in the progression of WT is summarized in this review.
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Affiliation(s)
- Jaber Alfaifi
- Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
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Pordel S, Khorrami M, Saadatpour F, Rezaee D, Cho WC, Jahani S, Aghaei-Zarch SM, Hashemi E, Najafi S. The role of microRNA-185 in the pathogenesis of human diseases: A focus on cancer. Pathol Res Pract 2023; 249:154729. [PMID: 37639952 DOI: 10.1016/j.prp.2023.154729] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/29/2023] [Indexed: 08/31/2023]
Abstract
MicroRNAs (miRNAs) are a widely-studied class of non-coding RNAs characterized by their short length (18-25 nucleotides). The precise functions of miRNAs are not well-elucidated; however, an increasing number of studies suggest their involvement in various physiologic processes and deregulation in pathologic conditions. miRNA-185 (miR-185) is among the mostly-studied miRNAs in human diseases, which is found to play putative roles in conditions like metabolic disorders, asthma, frailty, schizophrenia, and hepatitis. Notably, many cancer studies report the downregulation of miR-185 in cell lines, tumor tissues, and plasma specimens of patients, while it demonstrates a suppressing role on the malignant properties of cancer cells in vitro and in vivo. Accordingly, miR-185 can be considered a tumor suppressor miRNA in human malignancies, while a few studies also report inconsistent findings. Being suggested as a prognostic/diagnostic biomarker, mi-185 is also found to offer clinical potentials, particularly for early diagnosis and prediction of the prognosis of cancer patients. In this review, we have outlined the studies that have evaluated the functions and clinical significance of miR-185 in different human diseases with a particular focus on cancer.
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Affiliation(s)
- Safoora Pordel
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology and Allergy, The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Motahare Khorrami
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Saadatpour
- Pharmaceutical Biotechnology Lab, Department of Microbiology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
| | | | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Hashemi
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Song B, Cao Q, Li T, Liu Y, Sun Q, Fan S, Li X. Biomarker identification of chronic atrophic gastritis and its potential drug analysis. FRONTIERS IN GASTROENTEROLOGY 2022; 1. [DOI: 10.3389/fgstr.2022.948323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
BackgroundChronic atrophic gastritis (CAG) is the first step of gastric precancerous lesions, and the study of the pathogenesis of CAG is helpful for the prevention and treatment of gastric cancer(GC). The purpose of this study is to explore the potential biomarkers and therapeutic drugs of CAG through bioinformatics analysis.MethodsThe GSE11632 dataset was downloaded from Gene Expression Omnibus (GEO) database and the differentially expressed genes (DEGs) were obtained by using GEO2R online tool. We searched GeneCard and DisGeNET databases for genes related to CAG and used the overlapping genes as final DEGs for further functional enrichment analysis and Protein-protein Interaction (PPI) network analysis. Tissue-specific expressed genes were identified by BioGPS database. Cytoscape software was used to identify key hub genes and validated them in GSE27411 data sets. The upstream miRNAs of hub gene was predicted by TargetScan, miRDB and miRWalk. Finally, run the Connectivity Map (CMap) to identify new potential drugs for the treatment of CAG.ResultsA total of 430 differentially expressed mRNA were identified in this study, including 315 up-regulated genes and 115 down-regulated genes. After intersecting with CAG-related genes in GeneCard and DisGeNET databases, 42 DEGs were obtained. 24 DEGs were identified as tissue-specific expressed genes, most of which were expressed in stomach. GO and KEGG pathway analysis showed that DGEs was mainly enriched in digestion, IL-1 production, gastric acid secretion and so on. A total of 6 hub genes were generated by cytoHubba plug-in, among which ATP4A, CFTR and EPCAM had high diagnostic value. A total of 13 overlapping miRNA were predicted by 6 hub genes.ConclusionATP4A, CFTR and EPCAM may be potential biomarkers of CAG. hsa-miR-185-5p-CFTR, hsa-miR-4644-CFTR and hsa-miR-4505-CFTR are potential RNA regulatory pathways to control the progression of CAG disease. Finally, amonafide, etoposide, mycophenolate-mofetil, cycloheximide and Emetine may be potential therapeutic drugs for CAG.
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Tan W, Wang G, Liu G, You D, Wei M, Jin X, Zhao W, Zheng M. The elevation of miR-185-5p alleviates high-fat diet-induced atherosclerosis and lipid accumulation in vivo and in vitro via SREBP2 activation. Aging (Albany NY) 2022; 14:1729-1742. [PMID: 35172278 PMCID: PMC8908921 DOI: 10.18632/aging.203896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 01/25/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVE SREBP2, a member of the SREBP family, is a primary regulator of lipid metabolism. In recent years, an increasing number of studies have suggested that miRNAs regulate lipid metabolism-related genes. It was speculated in this study that miRNAs may be implicated in the regulation of lipid accumulation in macrophages by SREBP2 protein. METHODS AND RESULTS GSE34812, GSE132651 and GSE28829 datasets comprised of atherosclerosis samples were downloaded to explore the gene expression profiles related to the miRNAs and SREBP2, and miR-185-5p was predicted to be a target of SREBP2. The GO annotations and KEGG pathway analysis were adopted for functional classification of differentially expressed genes, and lipid metabolic process was an enriched pathway in atherosclerosis. Besides, the effects of SREBP2 on increasing lipid accumulation were investigated in vivo using miR-185-5p mimic/apoE-/- mice and miR-185-5p NC/apoE-/- mice. All mice fed with a HFD suffered from atherosclerosis. Moreover, the effects of miR-185-5p on atherosclerotic plaque formation in mice were analyzed. An in vitro assay was also performed to determine the effect of miR-185-5p on ox-LDL-stimulated RAW 264.7 macrophages. Finally, miR-185-5p mimic was transfected into cultured macrophages. The results showed that the miR-185-5p elevation might regulate lipid accumulation in mice by targeting SREBP2. Furthermore, miR-185-5p mimic repressed the activation of SREBP1, SREBP2, LDLR, SCD-1, HMGCR as well as NLRP3, IL-1β, TNF-α in HFD fed mice or ox-LDL-stimulated macrophages. CONCLUSIONS our study demonstrated that miR-185-5p effectively alleviates atherosclerosis and lipid accumulation by regulating the miR-185-5p/SREBP2 axis.
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Affiliation(s)
- Wenyun Tan
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Gang Wang
- Department of Cardiology, 980 Hospital of PLA Joint Logistics Support Forces, Shijiazhuang, Hebei, China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Daofeng You
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Mei Wei
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaojing Jin
- Department of Emergency, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wei Zhao
- Department of Ultrasound, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Mingqi Zheng
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Park JR, Ahn JH, Jung MH, Kim JH, Kang MG, Kim KH, Jang JY, Park HW, Koh JS, Hwang SJ, Park Y, Jeong YH, Kwak CH, Hwang JY. Serum microRNA-185 Levels and Myocardial Injury in Patients with Acute ST-segment Elevation Myocardial Infarction. Intern Med 2022; 61:151-158. [PMID: 34248121 PMCID: PMC8851187 DOI: 10.2169/internalmedicine.7594-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Human microRNA-185 (miR-185) has been reported to act as a regulator of fibrosis and angiogenesis in cancer. However, miR-185 has not been investigated in patients with ST-segment elevation myocardial infarction (STEMI). We hypothesized that the changes in miR-185 levels in STEMI patients are related to the processes of myocardial healing and remodeling. Methods Between January 2011 and December 2013, 145 patients with STEMI (65.9±11.6 years old; 41 women) were enrolled. Initial and discharge serum samples collected from 20 patients with STEMI and mixed sera from 8 healthy controls were analyzed by a microarray. A quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of miR-185 was performed in all 145 patients. The correlation between the miR-185 levels and the clinical, laboratory, angiographic, and echocardiographic parameters was analyzed. Results The microarray analysis revealed a biphasic pattern in miR-185 levels, with an initial decrease followed by an increase at discharge. The miR-185 levels at discharge were significantly correlated with the troponin-I, CK-MB, and area under the curve of CK-MB levels. There was a positive correlation between the transforming growth factor-β and miR-185 levels at discharge (ρ=0.242, p=0.026). A high wall motion score index and a low ejection fraction, as measured by echocardiography, and high B-type natriuretic peptide level at one month after STEMI were related to high miR-185 levels. Conclusion Our results showed that elevated miR-185 levels at the late stage of STEMI were related to a large amount of myocardial injury and adverse remodeling.
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Affiliation(s)
- Jeong Rang Park
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jong Hwa Ahn
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Myeong Hee Jung
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Biomedical Research Institute, Gyeongsang National University Hospital, Republic of Korea
| | - Jin Hyun Kim
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Biomedical Research Institute, Gyeongsang National University Hospital, Republic of Korea
| | - Min Gyu Kang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Kye Hwan Kim
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jeong Yoon Jang
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Hyun Woong Park
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jin-Sin Koh
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Seok-Jae Hwang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Yongwhi Park
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Young-Hoon Jeong
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Choong Hwan Kwak
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Jin-Yong Hwang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
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Luteolin and cancer metastasis suppression: focus on the role of epithelial to mesenchymal transition. Med Oncol 2021; 38:66. [PMID: 33950369 DOI: 10.1007/s12032-021-01508-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/05/2021] [Indexed: 02/07/2023]
Abstract
Epithelial to mesenchymal transition (EMT) is a physiological process that assumes a primary role in the induction of cancer metastasis. This results in increased cell renewal, and resistance to cell death and therapies. EMT, therefore, represents an effective strategy for regulating cancerous cell activity. A need for efficacy and low cytotoxicity epithelial to mesenchymal transition modifying drugs has led to the investigational testing of the efficacy of plethora of different groups of phytonutrients. Luteolin is a natural flavonoid inhibits the growth of cancer cells by various mechanisms, such as the stimulation of cancer cell apoptosis, cell cycle arrest, inhibition of cell replication, tumor growth, improvement of drug resistance, prevention of cancer cell intrusiveness and metastasis. This review article focuses on the anti-cancer and anti-metastatic potential of luteolin targeting various transcription factors, markers and signaling pathways associated with the repression of epithelial to mesenchymal transition.
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Sun J, Zhao J, Yang Z, Zhou Z, Lu P. Identification of gene signatures and potential therapeutic targets for acquired chemotherapy resistance in gastric cancer patients. J Gastrointest Oncol 2021; 12:407-422. [PMID: 34012635 PMCID: PMC8107589 DOI: 10.21037/jgo-21-81] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is the most common type of gastrointestinal cancer, and has been studied extensively. However, resistance to chemotherapeutic agents has become a major problem, leading to treatment failure. This study aimed to investigate the molecular mechanisms mediating acquired resistance to cisplatin and fluorouracil (CF) combination-based chemotherapy in GC patients. METHODS The microarray datasets (GSE14209, GSE30070) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) using the limma package in R/Bioconductor. Possible targets of the DEMs were predicted using miRWalk, and the putative miRNA-mRNA regulatory network was constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were then conducted and visualized using the Search Tool for Retrieval of Interacting Genes (STRING) and Cytoscape. The prognostic value of hub genes was revealed by Kaplan-Meier Plotter. The causal relationships and interactions between proteins were displayed using DisNor. Finally, similarity analysis was conducted using the Connectivity Map (CMap) profiles to predict a group of small molecules in GC treatment. RESULTS A total of 394 DEGs and 31 DEMs were identified after analysis of pre- and post-treatment samples of clinical responders to CF therapy. TM9SF4, hsa-miR-185-5p, and hsa-miR-145-5p were found to be critical in the miRNA-mRNA regulatory network. The DEGs were found to be mainly enriched in the processes of ribonucleoprotein complex assembly, catalytic activity acting on RNA, mitochondrial matrix, and thermogenesis. The DEMs were predominantly found to be involved in single-stranded RNA binding and endoplasmic reticulum lumen. HDAC5, DDX17, ILF3, and SDHC were identified as hub genes in the PPI network. Of these, HDAC5, DDX17, and ILF3 were found to be closely related to the overall survival of GC patients. DisNor identified the first neighbors of the key genes. Furthermore, CMap profiles predicted a group of small molecules, including several histone deacetylase inhibitors (HDACIs), menadione, and mibefradil, which could serve as promising therapeutic agents to reverse acquired resistance to CF therapy. CONCLUSIONS Our findings reveal new targets and alternative therapies to overcome the acquired resistance of GC patients to CF treatment.
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Affiliation(s)
- Jie Sun
- Center of Clinical Research, Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Jingjing Zhao
- Center of Clinical Research, Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Zhenkun Yang
- Center of Clinical Research, Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Zhiyi Zhou
- Department of Pathology, Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Peihua Lu
- Department of Medical Oncology, Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
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Li Y, Zhao Y, Li Y, Zhang X, Li C, Long N, Chen X, Bao L, Zhou J, Xie Y. Gastrin-17 induces gastric cancer cell epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway. J Physiol Biochem 2021; 77:93-104. [PMID: 33625675 DOI: 10.1007/s13105-020-00780-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis.
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Affiliation(s)
- YaJie Li
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - Yi Li
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - XiaoYi Zhang
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - Chao Li
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - NiYa Long
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - XueShu Chen
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
| | - LiYa Bao
- Affiliated Hospital, Guiyang Medical University, No. 9, Beijing Road, Guiyang, 550004, China
| | - JianJiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China
- Affiliated Hospital, Guiyang Medical University, No. 9, Beijing Road, Guiyang, 550004, China
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guizhou, China.
- Key Laboratory of Medical Molecular Biology (Guizhou Medical University), No. 9, Beijing Road, Guiyang, 550004, China.
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Liu J, Han Y, Liu X, Wei S. Serum miR-185 Is a Diagnostic and Prognostic Biomarker for Non-Small Cell Lung Cancer. Technol Cancer Res Treat 2020; 19:1533033820973276. [PMID: 33251978 PMCID: PMC7705799 DOI: 10.1177/1533033820973276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) have been found to play important roles in the development of non-small cell lung carcinoma (NSCLC). The aim of this study was to analyze the expression and clinical value of serum miR-185 in NSCLC. METHODS Serum miR-185 levels were detected in 146 NSCLC patients, 50 patients with carcinoma in situ, 25 patients with non-malignant lung diseases (NMLD), and 80 healthy controls using quantitative reverse transcription PCR. The correlation between serum miR-185 level and clinical status of NSCLC was explored. RESULTS The results revealed that serum miR-185 expression was progressively decreased in healthy controls, patients with NMLD, patients with carcinoma in situ and NSCLC patients. In addition, compared to carcinoembryonic antigen (CEA), serum miR-185 demonstrated better diagnostic accuracy for discriminating patients with carcinoma from healthy controls, NSCLC patients from healthy controls and NSCLC patients from patients with carcinoma in situ. In addition, serum miR-185 levels were significantly elevated in post-treated samples compared to the pre-treated samples. Moreover, reduced serum miR-185 was closely associated with unfavorable clinicopathological parameters and worse survival. Univariate and multivariate cox regression analysis confirmed that serum miR-185 was an independent prognostic indicator for NSCLC. CONCLUSIONS Collectively, our findings have demonstrated that serum miR-185 might serve as a promising and robust biomarker for the early detection and prognosis prediction of NSCLC.
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Affiliation(s)
- Jinghao Liu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
| | - Yueting Han
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin City, China
| | - Xingyu Liu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
| | - Sen Wei
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
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11
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Wang W, Li Y, Zhi S, Li J, Miao J, Ding Z, Peng Y, Huang Y, Zheng R, Yu H, Qi P, Wang J, Fu X, Hu M, Chen S. LncRNA-ROR/microRNA-185-3p/YAP1 axis exerts function in biological characteristics of osteosarcoma cells. Genomics 2020; 113:450-461. [PMID: 32898639 DOI: 10.1016/j.ygeno.2020.09.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/21/2020] [Accepted: 09/03/2020] [Indexed: 11/19/2022]
Abstract
AIM The co-expression network of long non-coding RNA ROR (lncRNA-ROR) and microRNA-185-3p (miR-185-3p) has not been focused on osteosarcoma. Therein, this work was initiated to uncover lncRNA-ROR and miR-185-3p functions in osteosarcoma. METHODS LncRNA-ROR, miR-185-3p and Yes-associated protein 1 (YAP1) expression in osteosarcoma tissues and cells were detected. The screened cells (MG63 and U2OS) were transfected with decreased and/or increased lncRNA-ROR and miR-185-3p to explore osteosarcoma progression. Tumor growth was detected by tumor xenografts in mice. RESULTS Up-regulated lncRNA-ROR and YAP1 and down-regulated miR-185-3p were found in osteosarcoma. LncRNA ROR knockdown or miR-185-3p overexpression inhibited osteosarcoma cell progression while lncRNA ROR elevation or miR-185-3p inhibition presented the opposite effects. Function of lncRNA ROR was rescued by miR-185-3p and regulated the growth and metastasis of osteosarcoma cells via modulating YAP1, the target gene of miR-185-3p. CONCLUSION This work illustrates that lncRNA-ROR down-regulation or miR-185-3p up-regulation inhibits osteosarcoma progression via YAP1 repression.
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Affiliation(s)
- Weiguo Wang
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yuezhan Li
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Shuang Zhi
- Four Gynecological Wards, Ningbo Women & Children's Hospital, Ningbo 315000, Zhejiang, China
| | - Jinsong Li
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jinglei Miao
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Zhiyu Ding
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yi Peng
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yan Huang
- The Second Xiangya Hospital of Central South University, Changsha 410013, Hunan, China
| | - Ruping Zheng
- School of Basic Medical Science, Central South University, Changsha 410013, Hunan, China
| | - Haiyang Yu
- School of Basic Medical Science, Central South University, Changsha 410013, Hunan, China
| | - Pei Qi
- Department of pharmacy, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China
| | - Jianlong Wang
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xingchang Fu
- Department of Orthopedics, Hunan Aerospace hospital, Changsha 410205, Hunan, China
| | - Minghua Hu
- Department of Anatomy, Histology and Embryology, Changsha Medical University, Changsha 410219, China
| | - Shijie Chen
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
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12
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MiR-185 targets POT1 to induce telomere dysfunction and cellular senescence. Aging (Albany NY) 2020; 12:14791-14807. [PMID: 32687062 PMCID: PMC7425516 DOI: 10.18632/aging.103541] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 06/01/2020] [Indexed: 12/20/2022]
Abstract
Protection of telomere 1 (POT1), the telomeric single-stranded DNA (ssDNA)-binding protein in the shelterin complex, has been implicated in the DNA damage response, tumorigenesis and aging. Telomere dysfunction induced by telomere deprotection could accelerate cellular senescence in primary human cells. While previous work demonstrated the biological mechanism of POT1 in aging and cancer, how POT1 is posttranscriptionally regulated remains largely unknown. To better understand the POT1 regulatory axis, we performed bioinformatic prediction, and selected candidates were further confirmed by dual-luciferase reporter assay. Collectively, our results revealed that miR-185 can significantly reduce POT1 mRNA and protein levels by directly targeting the POT1 3’-untranslated region (3’-UTR). Overexpression of miR-185 increased telomere dysfunction-induced foci (TIF) signals in both cancer cells and primary human fibroblasts. Elevated miR-185 led to telomere elongation in the telomerase-positive cell line HTC75, which was phenotypically consistent with POT1 knocking down. Moreover, miR-185 accelerated the replicative senescence process in primary human fibroblasts in a POT1-dependent manner. Interestingly, increased serum miR-185 could represent a potential aging-related biomarker. Taken together, our findings reveal miR-185 as a novel aging-related miRNA that targets POT1 and provide insight into the telomere and senescence regulatory network at both the intracellular and extracellular levels.
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13
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Wu J, Yang Y, Cheng L, Wu J, Xi L, Ma Y, Zhang P, Xu X, Zhang D, Li S. GCdiscrimination: identification of gastric cancer based on a milliliter of blood. Brief Bioinform 2020; 22:536-544. [PMID: 32010933 DOI: 10.1093/bib/bbaa006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/22/2019] [Accepted: 11/21/2019] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) continues to be one of the major causes of cancer deaths worldwide. Meanwhile, liquid biopsies have received extensive attention in the screening and detection of cancer along with better understanding and clinical practice of biomarkers. In this work, 58 routine blood biochemical indices were tentatively used as integrated markers, which further expanded the scope of liquid biopsies and a discrimination system for GC consisting of 17 top-ranked indices, elaborated by random forest method was constructed to assist in preliminary assessment prior to histological and gastroscopic diagnosis based on the test data of a total of 2951 samples. The selected indices are composed of eight routine blood indices (MO%, IG#, IG%, EO%, P-LCR, RDW-SD, HCT and RDW-CV) and nine blood biochemical indices (TP, AMY, GLO, CK, CHO, CK-MB, TG, ALB and γ-GGT). The system presented a robust classification performance, which can quickly distinguish GC from other stomach diseases, different cancers and healthy people with sensitivity, specificity, total accuracy and area under the curve of 0.9067, 0.9216, 0.9138 and 0.9720 for the cross-validation set, respectively. Besides, this system can not only provide an innovative strategy to facilitate rapid and real-time GC identification, but also reveal the remote correlation between GC and these routine blood biochemical parameters, which helped to unravel the hidden association of these parameters with GC and serve as the basis for subsequent studies of the clinical value in prevention program and surveillance management for GC. The identification system, called GC discrimination, is now available online at http://lishuyan.lzu.edu.cn/GC/.
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Affiliation(s)
| | | | | | | | - Lili Xi
- First Hospital of Lanzhou University
| | - Ying Ma
- physician in Gansu Provincial Maternity and Child-care Hospital
| | | | - Xiaoying Xu
- physician of First Hospital of Lanzhou University
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14
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Codolo G, Toffoletto M, Chemello F, Coletta S, Soler Teixidor G, Battaggia G, Munari G, Fassan M, Cagnin S, de Bernard M. Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA. Front Immunol 2020; 10:2923. [PMID: 31969878 PMCID: PMC6960189 DOI: 10.3389/fimmu.2019.02923] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 11/28/2019] [Indexed: 12/17/2022] Open
Abstract
Macrophages have a major role in infectious and inflammatory diseases, and the available data suggest that Helicobacter pylori persistence can be explained in part by the failure of the bacterium to be killed by professional phagocytes. Macrophages are cells ready to kill the engulfed pathogen, through oxygen-dependent and -independent mechanisms; however, their killing potential can be further augmented by the intervention of T helper (Th) cells upon the specific recognition of human leukocyte antigen (HLA)-II-peptide complexes on the surface of the phagocytic cells. As it pertains to H. pylori, the bacterium is engulfed by macrophages, but it interferes with the phagosome maturation process leading to phagosomes with an altered degradative capacity, and to megasomes, wherein H. pylori resists killing. We recently showed that macrophages infected with H. pylori strongly reduce the expression of HLA-II molecules on the plasma membrane and this compromises the bacterial antigen presentation to Th lymphocytes. In this work, we demonstrate that H. pylori hampers HLA-II expression in macrophages, activated or non-activated by IFN-γ, by down-regulating the expression of the class II major histocompatibility complex transactivator (CIITA), the "master control factor" for the expression of HLA class II genes. We provided evidence that this effect relies on the up-regulation of let-7f-5p, let-7i-5p, miR-146b-5p, and -185-5p targeting CIITA. MiRNA expression analysis performed on biopsies from H. pylori-infected patients confirmed the up-regulation of let-7i-5p, miR-146b-5p, and -185-5p in gastritis, in pre-invasive lesions, and in gastric cancer. Taken together, our results suggest that specific miRNAs may be directly involved in the H. pylori infection persistence and may contribute to confer the risk of developing gastric neoplasia in infected patients.
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Affiliation(s)
- Gaia Codolo
- Department of Biology, University of Padua, Padua, Italy
| | | | - Francesco Chemello
- Department of Biology, University of Padua, Padua, Italy
- CRIBI Biotechnology Center, University of Padua, Padua, Italy
| | - Sara Coletta
- Department of Biology, University of Padua, Padua, Italy
| | | | | | - Giada Munari
- Istituto Oncologico Veneto (IRCCS), Padua, Italy
| | - Matteo Fassan
- Department of Medicine, University of Padua, Padua, Italy
| | - Stefano Cagnin
- Department of Biology, University of Padua, Padua, Italy
- CRIBI Biotechnology Center, University of Padua, Padua, Italy
- CIR-Myo Myology Center, University of Padua, Padua, Italy
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15
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Chen Z, Zhang Z, Zhao D, Feng W, Meng F, Han S, Lin B, Shi X. Long Noncoding RNA (lncRNA) FOXD2-AS1 Promotes Cell Proliferation and Metastasis in Hepatocellular Carcinoma by Regulating MiR-185/AKT Axis. Med Sci Monit 2019; 25:9618-9629. [PMID: 31841454 PMCID: PMC6929557 DOI: 10.12659/msm.918230] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the effects and mechanisms of long noncoding (lnc) RNA FOXD2-AS1 in hepatocellular carcinoma development. MATERIAL AND METHODS Collecting the 3 pairs of adjacent and hepatocellular carcinoma tissue and analysis by gene chip. Evaluating the FOXD2-AS1 expression by in situ hybridization assay. Evaluating the FOXD2-AS1 to Bel-7402 biological activity in vitro study by Cell Counting Kit-8, flow cytometry, Transwell and wound healing assay and correlation between miR-185 by dual-luciferase reporter assay. The relative proteins expressions were evaluated by western blot assay. RESULTS FOXD2-AS1 was significantly upregulation in hepatocellular carcinoma tissues. FOXD2-AS1 knockdown suppressed Bel-7401 cell biological activities (proliferation, invasion, and migration) with miR-185 overexpression and AKT depressing in cell expression. CONCLUSIONS LncRNA FOXD2-AS1 promoted hepatocellular carcinoma development by regulation miR-185/AKT axis.
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Affiliation(s)
- Zheng Chen
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Zhen Zhang
- Department of Anesthesiology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Dongbo Zhao
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Wei Feng
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Fanlai Meng
- Department of Pathology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Shihui Han
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Bin Lin
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
| | - Xin Shi
- Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian People's Hospital of Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, China (mainland)
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16
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Wang SJ, Li YJ, Gao B, Li XL, Li YT, He HY. Long non-coding RNA 00152 slicing represses the growth and aggressiveness of hemangioma cell by modulating miR-139-5p. Biomed Pharmacother 2019; 120:109385. [DOI: 10.1016/j.biopha.2019.109385] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/08/2019] [Accepted: 08/22/2019] [Indexed: 12/20/2022] Open
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17
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Yuan Z, Zhong L, Liu D, Yao J, Liu J, Zhong P, Yao S, Zhao Y, Li L, Chen M, Liu L, Liu B. MiR-15b regulates cell differentiation and survival by targeting CCNE1 in APL cell lines. Cell Signal 2019; 60:57-64. [PMID: 30965092 DOI: 10.1016/j.cellsig.2019.04.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/21/2019] [Accepted: 04/05/2019] [Indexed: 01/19/2023]
Abstract
MicroRNAs have been shown to be involved in various cell processes, including proliferation, apoptosis and differentiation. However, little is known about their function in granulopoiesis. In the present study, overexpression and knockdown experiments revealed that miR-15b was required to block the proliferation of NB4 and HL60 cells and induce them differentiated to granulocyte lineage. Moreover, we identified CCNE1 as a direct target of miR-15b, and demonstrated that CCNE1 was involved in cell differentiation and proliferation in acute promyelocytic leukemia cells. In addition, we demonstrated a novel pathway in which miR-15b regulated cells arrested in the G0/G1 phase and promoted terminal differentiation of cells by targeting CCNE1, which could modulate the cell cycle effort pRb in APL cells. These events blocked cell proliferation and promoted granulocyte differentiation. In conclusion, our data highlighted, for the first time, the important role of miR-15b in myeloid differentiation and suggested the potential role of miR-15b in cancer therapy.
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Affiliation(s)
- Zhen Yuan
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Liang Zhong
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Dongdong Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Juanjuan Yao
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Junmei Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Pengqiang Zhong
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Shifei Yao
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Yi Zhao
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Lianwen Li
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Min Chen
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Lu Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Beizhong Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
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18
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Li Y, Cui X, Li Y, Zhang T, Li S. Upregulated expression of miR-421 is associated with poor prognosis in non-small-cell lung cancer. Cancer Manag Res 2018; 10:2627-2633. [PMID: 30147363 PMCID: PMC6095112 DOI: 10.2147/cmar.s167432] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Non-small-cell lung cancer (NSCLC) represents the most frequent subtype of lung cancer. MicroRNAs (miRNAs) have attracted a lot of attention with regard to their clinical significance and crucial biological functions in various human cancers. This study aimed to investigate the prognostic significance of microRNA-421 (miR-421) and its correlation with tumor progression in NSCLC. Materials and methods Expression levels of miR-421 in both serum and tissue samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The prognostic value of miR-421 was evaluated using Kaplan–Meier survival analysis and Cox regression assay. To explore the functional role of miR-421 during NSCLC progression, cell experiments were carried out. Results Expression of serum and tissue miR-421 was upregulated in the NSCLC patients compared with the normal controls (all P<0.001), and the expression showed a significant correlation between the serum samples and tissues (R=0.475, P<0.001). The increased miR-421 expression was associated with positive lymph-node metastasis and advanced TNM stage (all P<0.05). Moreover, patients with high miR-421 expression had poor overall survival compared with those with low expression (log-rank P=0.007). The overexpression of miR-421 proved to be an independent prognostic factor for NSCLC (HR=1.991, 95% CI=1.046–3.791, P=0.036). According to the cell experiments, the proliferation, migration and invasion of NSCLC cells were suppressed by knockdown of miR-421. Conclusion Overexpression of miR-421 serves as a prognostic biomarker and may be involved in the promotion of tumor progression in NSCLC.
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Affiliation(s)
- Yunxia Li
- Department of Clinical Laboratory, Shouguang People's Hospital, Shandong 262700, China,
| | - Xiaomei Cui
- Department of Neurosurgery, Shouguang People's Hospital, Shandong 262700, China
| | - Yongdeng Li
- Department of Joint Surgery, Shouguang People's Hospital, Shandong 262700, China
| | - Tingting Zhang
- Hemodialysis Room, Shouguang People's Hospital, Shandong 262700, China
| | - Shuyun Li
- Coronary Care Unit, Shouguang People's Hospital, Shandong 262700, China
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Optimizing miRNA-module diagnostic biomarkers of gastric carcinoma via integrated network analysis. PLoS One 2018; 13:e0198445. [PMID: 29879180 PMCID: PMC5991748 DOI: 10.1371/journal.pone.0198445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/18/2018] [Indexed: 12/17/2022] Open
Abstract
Several microRNAs (miRNAs) have been suggested as novel biomarkers for diagnosing gastric cancer (GC) at an early stage, but the single-marker strategy may ignore the co-regulatory relationships and lead to low diagnostic specificity. Thus, multi-target modular diagnostic biomarkers are urgently needed. In this study, a Zsummary and NetSVM-based method was used to identify GC-related hub miRNAs and activated modules from clinical miRNA co-expression networks. The NetSVM-based sub-network consisting of the top 20 hub miRNAs reached a high sensitivity and specificity of 0.94 and 0.82. The Zsummary algorithm identified an activated module (miR-486, miR-451, miR-185, and miR-600) which might serve as diagnostic biomarker of GC. Three members of this module were previously suggested as biomarkers of GC and its 24 target genes were significantly enriched in pathways directly related to cancer. The weighted diagnostic ROC AUC of this module was 0.838, and an optimized module unit (miR-451 and miR-185) obtained a higher value of 0.904, both of which were higher than that of individual miRNAs. These hub miRNAs and module have the potential to become robust biomarkers for early diagnosis of GC with further validations. Moreover, such modular analysis may offer valuable insights into multi-target approaches to cancer diagnosis and treatment.
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20
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Zhang W, Sun Z, Su L, Wang F, Jiang Y, Yu D, Zhang F, Sun Z, Liang W. miRNA-185 serves as a prognostic factor and suppresses migration and invasion through Wnt1 in colon cancer. Eur J Pharmacol 2018; 825:75-84. [PMID: 29454608 DOI: 10.1016/j.ejphar.2018.02.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 02/06/2018] [Accepted: 02/14/2018] [Indexed: 02/06/2023]
Abstract
Colon cancer is one of the deadliest cancers worldwide; abnormal microRNA expression is common during colon cancer development. The aim of the present study was to elucidate the role played by miR-185 in this context. We used quantitative real-time PCR (qRT-PCR) to measure miR-185 expression levels in colon cancer cell lines. The effects of miR-185 on colon cancer cell proliferation and invasion were assessed using the MTT, colony-forming, wound-healing, and transwell assays. A luciferase activity assay was used to confirm the target of miR-185. Our data showed that miR-185 was significantly down-regulated in colon cancer cells and colonic cancer tissues compared with NCM460 normal colonic epithelial cells and adjacent normal tissues. A functional analysis revealed that ectopic expression of miR-185 significantly inhibited colon cancer cell proliferation, colony formation, migration, and invasion. In addition, western blot, qRT-PCR, and luciferase assays confirmed in colon cancer cells that Wnt1 was a downstream target of miR-185, in turn suppressing β-catenin-mediated signaling. In conclusion, we found that miR-185 inhibits colon cancer cell proliferation and invasion by targeting Wnt1, and that it serves as a tumor suppressor, indicating that the modulation of miR-185 levels may potentially be therapeutic in colon cancer patients.
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Affiliation(s)
- Wenjun Zhang
- Department of Colorectal Surgery, Xinhua Affiliated Hospital of Dalian University, Dalian 116021, China
| | - Zheng Sun
- Department of Endocrinology, The Second Hospital of Dalian Medical University, Dalian116023, China
| | - Liang Su
- Department of Oncology, Medical College of Dalian University, Dalian 116622, China
| | - Feng Wang
- Department of Colorectal Surgery, Xinhua Affiliated Hospital of Dalian University, Dalian 116021, China
| | - Yiming Jiang
- Department of Oncology, Medical College of Dalian University, Dalian 116622, China
| | - Dengfeng Yu
- Department of Colorectal Surgery, Xinhua Affiliated Hospital of Dalian University, Dalian 116021, China
| | - Fujie Zhang
- Department of Colorectal Surgery, Xinhua Affiliated Hospital of Dalian University, Dalian 116021, China
| | - Zhe Sun
- Department of Colorectal Surgery, Xinhua Affiliated Hospital of Dalian University, Dalian 116021, China
| | - Wenbo Liang
- Department of Oncology, Medical College of Dalian University, Dalian 116622, China.
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Soliman AM, Das S, Abd Ghafar N, Teoh SL. Role of MicroRNA in Proliferation Phase of Wound Healing. Front Genet 2018; 9:38. [PMID: 29491883 PMCID: PMC5817091 DOI: 10.3389/fgene.2018.00038] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/29/2018] [Indexed: 12/15/2022] Open
Abstract
Wound healing is a complex biological process that is generally composed of four phases: hemostasis, inflammation, proliferation, and remodeling. The proliferation phase is crucial for effective healing compared to other phases. Many critical events occur during this phase, i.e., migration of fibroblasts, re-epithelialization, angiogenesis and wound contraction. Chronic wounds are common and are considered a major public health problem. Therefore, there is the increasing need to discover new therapeutic strategies. MicroRNA (miRNA) research in the field of wound healing is in its early phase, but the knowledge of the recent discoveries is essential for developing effective therapies for the treatment of chronic wounds. In this review, we focused on recently discovered miRNAs which are involved in the proliferation phase of wound healing in the past few years and their role in wound healing.
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Affiliation(s)
| | | | | | - Seong Lin Teoh
- Department of Anatomy, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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Lei Z, Shi H, Li W, Yu D, Shen F, Yu X, Lu D, Sun C, Liao K. miR‑185 inhibits non‑small cell lung cancer cell proliferation and invasion through targeting of SOX9 and regulation of Wnt signaling. Mol Med Rep 2018; 17:1742-1752. [PMID: 29138830 PMCID: PMC5780119 DOI: 10.3892/mmr.2017.8050] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 10/10/2017] [Indexed: 12/15/2022] Open
Abstract
SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non‑small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR‑185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR‑185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR‑185. In addition, the downstream Wnt signaling‑associated factors β‑catenin and c‑Myc proto‑oncogene protein (Myc) were demonstrated to be inhibited by miR‑185 overexpression. SOX9, β‑catenin and c‑Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR‑185 expression. The results of the present study demonstrated that rescuing miR‑185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC.
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Affiliation(s)
- Zhengwen Lei
- Department of Cardiac-Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of Cardiac-Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225000, P.R. China
| | - Hongcan Shi
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of Cardiac-Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225000, P.R. China
- Correspondence to: Professor Hongcan Shi, Center of Translational Medicine, Medical School of Yangzhou University, 11 Huaihai Road, Yangzhou, Jiangsu 225000, P.R. China, E-mail:
| | - Wei Li
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Duonan Yu
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Feiyang Shen
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Xi Yu
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Dan Lu
- Department of Obstetrical, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225000, P.R. China
| | - Chao Sun
- Department of Cardiac-Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225000, P.R. China
| | - Kai Liao
- Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
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Kim M, Kogan N, Slack FJ. Cis-acting elements in its 3' UTR mediate post-transcriptional regulation of KRAS. Oncotarget 2017; 7:11770-84. [PMID: 26930719 PMCID: PMC4914247 DOI: 10.18632/oncotarget.7599] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 01/17/2016] [Indexed: 11/25/2022] Open
Abstract
Multiple RNA-binding proteins and non-coding RNAs, such as microRNAs (miRNAs), are involved in post-transcriptional gene regulation through recognition motifs in the 3' untranslated region (UTR) of their target genes. The KRAS gene encodes a key signaling protein, and its messenger RNA (mRNA) contains an exceptionally long 3' UTR; this suggests that it may be subject to a highly complex set of regulatory processes. However, 3' UTR-dependent regulation of KRAS expression has not been explored in detail. Using extensive deletion and mutational analyses combined with luciferase reporter assays, we have identified inhibitory and stabilizing cis-acting regions within the KRAS 3' UTR that may interact with miRNAs and RNA-binding proteins, such as HuR. Particularly, we have identified an AU-rich 49-nt fragment in the KRAS 3' UTR that is required for KRAS 3' UTR reporter repression. This element contains a miR-185 complementary element, and we show that overexpression of miR-185 represses endogenous KRAS mRNA and protein in vitro. In addition, we have identified another 49-nt fragment that is required to promote KRAS 3' UTR reporter expression. These findings indicate that multiple cis-regulatory motifs in the 3' UTR of KRAS finely modulate its expression, and sequence alterations within a binding motif may disrupt the precise functions of trans-regulatory factors, potentially leading to aberrant KRAS expression.
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Affiliation(s)
- Minlee Kim
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.,Institute for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
| | - Nicole Kogan
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.,Current address: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Frank J Slack
- Institute for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
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24
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Zhang Q, Chen B, Liu P, Yang J. XIST promotes gastric cancer (GC) progression through TGF‐β1 via targeting miR‐185. J Cell Biochem 2017; 119:2787-2796. [DOI: 10.1002/jcb.26447] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 10/17/2017] [Indexed: 01/05/2023]
Affiliation(s)
- Quan Zhang
- Department of OncologyThe First Affiliated HospitalNanjing Medical UniversityNanjingChina
- Department of Radiation OncologyHuai'an First People's HospitalNanjing Medical UniversityHuai'anChina
| | - Baiyu Chen
- Department of General SurgeryLian Shui People's HospitalLianshuiJiangsuChina
| | - Ping Liu
- Department of OncologyThe First Affiliated HospitalNanjing Medical UniversityNanjingChina
| | - Jing Yang
- Department of Radiation OncologyHuai'an First People's HospitalNanjing Medical UniversityHuai'anChina
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25
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Tan B, Li Y, Di Y, Fan L, Zhao Q, Liu Q, Wang D, Jia N. Clinical value of peripheral blood microRNA detection in evaluation of SOX regimen as neoadjuvant chemotherapy for gastric cancer. J Clin Lab Anal 2017; 32:e22363. [PMID: 29168576 DOI: 10.1002/jcla.22363] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 10/31/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Neoadjuvant chemotherapy has been widely applied in treating advanced gastric cancer (GC). However, little research has been conducted on evaluating the effect of neoadjuvant chemotherapy. Purpose of this study was to evaluate the effect of SOX regimen as neoadjuvant chemotherapy by detecting some microRNAs. METHODS Total 120 GC patients who had received neoadjuvant chemotherapy (SOX regimen) were recruited with 100 healthy participants as control contemporarily. Age and gender have no significant difference in both groups (P > .05). The effect of chemotherapy was evaluated by the results of CT scan and surgery. Also, adverse effects of chemotherapy were documented. Peripheral blood of GC patients was collected twice: one day before chemotherapy and surgery, respectively, whereas healthy controls' peripheral blood was collected once. Quantitative real-time PCR (qPCR) was utilized to detect expression of miR-145, miR-185, miR-381, and miR-195 of peripheral blood in both groups. RESULTS One hundred and twenty patients with advanced GC completed a total of 386 cycles of neoadjuvant chemotherapy with effective rate at 84.17% (101 of 120). Expression of miR-145, miR-185, and miR-381 of patients with GC was lower than that in the control group before chemotherapy commence (all P < .05), while the expressions of miR-145 and miR-185 elevated noticeably in CG patients after neoadjuvant chemotherapy (P < .05). The differences in the expression of miR-145 and miR-185 in advanced GC patients with different chemotherapy outcomes were detected. CONCLUSION Patients with GC at advanced stages had aberrant miRs expressions. Detection of miR-145 and miR-185 expression may assist to predict effectiveness and adverse effects of SOX regimen as neoadjuvant chemotherapy.
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Affiliation(s)
- Bibo Tan
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yan Di
- Hebei Provincial Institute of Medical Science Information, Shijiazhuang, China
| | - Liqiao Fan
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qun Zhao
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qingwei Liu
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dong Wang
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Nan Jia
- Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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26
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Zhang Y, Guan DH, Bi RX, Xie J, Yang CH, Jiang YH. Prognostic value of microRNAs in gastric cancer: a meta-analysis. Oncotarget 2017; 8:55489-55510. [PMID: 28903436 PMCID: PMC5589675 DOI: 10.18632/oncotarget.18590] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/08/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Previous articles have reported that expression levels of microRNAs (miRNAs) are associated with survival time of patients with gastric cancer (GC). A systematic review and meta-analysis was performed to study the outcome of it. DESIGN Meta-analysis. METHODS English studies estimating expression levels of miRNAs with any of survival curves in GC were identified up till March 19, 2017 through performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two authors independently. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). RESULTS Sixty-nine relevant articles about 26 miRNAs with 6148 patients were ultimately included. GC patients with high expression of miR-20b (HR=2.38, 95%CI=1.16-4.87), 21 (HR=1.77, 95%CI=1.01-3.08), 106b (HR=1.84, 95%CI=1.15-2.94), 196a (HR=2.66, 95%CI=1.94-3.63), 196b (HR=1.67, 95%CI=1.38-2.02), 214 (HR=1.84, 95%CI=1.27-2.67) or low expression of miR-125a (HR=2.06, 95%CI=1.26-3.37), 137 (HR=3.21, 95%CI=1.68-6.13), 141 (HR=2.47, 95%CI=1.34-4.56), 145 (HR=1.62, 95%CI=1.07-2.46), 146a (HR=2.60, 95%CI=1.63-4.13), 206 (HR=2.85, 95%CI=1.73-4.70), 218 (HR=2.61, 95%CI=1.74-3.92), 451 (HR=1.73, 95%CI=1.19-2.52), 486-5p (HR=2.45, 95%CI=1.65-3.65), 506 (HR=2.07, 95%CI=1.33-3.23) have significantly poor OS (P<0.05). CONCLUSIONS In summary, miR-20b, 21, 106b, 125a, 137, 141, 145, 146a, 196a, 196b, 206, 214, 218, 451, 486-5p and 506 demonstrate significantly prognostic value. Among them, miR-20b, 125a, 137, 141, 146a, 196a, 206, 218, 486-5p and 506 are strong biomarkers of prognosis in GC.
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Affiliation(s)
- Yue Zhang
- 1 First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong, People's Republic of China
| | - Dong-Hui Guan
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Rong-Xiu Bi
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Jin Xie
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Chuan-Hua Yang
- 3 Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Yue-Hua Jiang
- 4 Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
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27
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Zheng Q, Chen C, Guan H, Kang W, Yu C. Prognostic role of microRNAs in human gastrointestinal cancer: A systematic review and meta-analysis. Oncotarget 2017; 8:46611-46623. [PMID: 28402940 PMCID: PMC5542297 DOI: 10.18632/oncotarget.16679] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 03/09/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastrointestinal cancers (GICs) mainly including esophageal, gastric and colorectal cancer, are the most common cause of cancer-related death and lead into high mortality worldwide. We performed this systematic review and meta-analysis to elucidate relationship between multiple microRNAs (miRs) expression and survival of GIC patients. METHODS We searched a wide range of database. Fixed-effects and random-effects models were used to calculate the pooled hazard ratio values of overall survival and disease free survival. In addition, funnel plots were used to qualitatively analyze the publication bias and verified by Begg's test while it seems asymmetry. RESULTS 60 studies involving a total of 6225 patients (1271 with esophageal cancer, 3467 with gastric cancer and 1517 with colorectal cancer) were included in our meta-analysis. The pooled hazard ratio values of overall survival related to different miRs expression in esophageal, gastric, colorectal and gastrointestinal cancer were 2.10 (1.78-2.49), 2.02 (1.83-2.23), 2.54 (2.14-3.02) and 2.15 (1.99-2.31), respectively. We have identified a total of 59 miRs including 23 significantly up-regulated expression miRs (miR-214, miR-17, miR-20a, miR-200c, miR-107, miR-27a, etc.) and 36 significantly down-regulated expression miRs (miR-433, let-7g, miR-125a-5p, miR-760, miR-206, miR-26a, miR-200b, miR-185, etc.) correlated with poor prognosis in GIC patients. Moreover, 35 of them revealed mechanisms. CONCLUSION Overall, specific miRs are significantly associated with the prognosis of GIC patients and potentially eligible for the prediction of patients survival. It also provides a potential value for clinical decision-making development and may serve as a promising miR-based target therapy waiting for further elucidation.
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Affiliation(s)
- Qiang Zheng
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Changyu Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Traditional Medical University, Hefei, China
| | - Haiyang Guan
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Weibiao Kang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Changjun Yu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
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28
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Zhang L, Huang Z, Zhang H, Zhu M, Zhu W, Zhou X, Liu P. Prognostic value of candidate microRNAs in gastric cancer: A validation study. Cancer Biomark 2017; 18:221-230. [PMID: 27983528 DOI: 10.3233/cbm-160091] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Studies have reported the prognostic value of dysregulated microRNAs (miRNAs) in gastric cancer (GC). However, the results demonstrated so far are inconsistent. OBJECTIVE To better understand the miRNAs with prognostic relevance. METHODS Evaluable miRNAs were selected based on our selection criteria and further analyzed in formalin-fixed paraffin-embedded (FFPE) tissue samples of 169 GC patients using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS A total of 19 miRNAs were selected as candidate miRNAs. Among those miRNAs identified, high expression of miR-21-5p was related to poor overall survival (OS) and disease free survival (DFS) and was identified as an independent prognostic factor. Cases with high level of miR-200c-3p showed poor DFS. Subgroup analysis revealed that high expression of miR-21-5p and miR-222-3p was associated with poor OS and DFS in GC patients not received adjuvant chemotherapy. In male patients, high expression level of miR-21-5p was related to poor OS and DFS. CONCLUSIONS The present study confirmed that elevated level of miR-21-5p could serve as an independent predictor for poor OS and DFS of GC patients. Moreover, miR-200c-3p, miR-222-3p might also play important roles in the prognosis of GC patients. Further studies are warranted to validate our findings and identify the functions and mechanisms of these miRNAs.
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29
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Sonohara F, Inokawa Y, Hayashi M, Kodera Y, Nomoto S. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer. Oncol Lett 2017; 13:3363-3368. [PMID: 28529571 DOI: 10.3892/ol.2017.5912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/14/2017] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
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30
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Xiao K, Luo X, Wang X, Gao Z. MicroRNA‑185 regulates transforming growth factor‑β1 and collagen‑1 in hypertrophic scar fibroblasts. Mol Med Rep 2017; 15:1489-1496. [PMID: 28259900 PMCID: PMC5364971 DOI: 10.3892/mmr.2017.6179] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 11/30/2016] [Indexed: 12/22/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) and collagen type I (Col-1) serve a critical role in the development and progression of hypertrophic scarring (HS). The present study hypothesized that a post‑translational mechanism of microRNAs (miR) regulated the expression of TGF‑β1 and Col‑1 in HS fibroblasts (HSFBs). A collection of 20 HS tissues was compared with corresponding normal tissues from clinical patients, and the expression of miR‑185 was measured. Using PicTar, TargetScan and miRBase databases, it was identified that miR‑185 may be a regulator of TGF‑β1 and Col‑1 in humans. Based on these hypotheses, the expression of miR‑185, TGF‑β1 and Col‑1 in HS tissues was investigated. The results demonstrated that the expression of miR‑185 was markedly suppressed, and TGF‑β1 and Col‑1 levels were increased, in HS tissues. The expression levels of endogenous miR‑185 negatively correlated with the TGF‑β1 and Col‑1 mRNA levels (Pearson's correlation coefficient r=‑0.674, P<0.01 and r=‑0.590, P<0.01, respectively). In vitro, miR‑185 can regulate TGF‑β1 and Col‑1 through the predicted binding sites in its 3'‑untranslated region. miR‑185 had an effect on cell proliferation and apoptosis, thereby regulating HSFBs growth. In addition, miR‑185 gain‑of‑function decreased TGF‑β1 and Col‑1 protein expression, and miR‑185 loss‑of‑function increased TGF‑β1 and Col‑1 protein expression in HSFBs. In conclusion, overexpressed miR‑185 could inhibit HSFBs growth, and the underlying mechanism was mediated, at least partly, through the suppression of TGF‑β1 and Col‑1 expression. However, above all, miR‑185 might serve as a potential therapeutic approach for the treatment of HS.
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Affiliation(s)
- Kaiyan Xiao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Xusong Luo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Xiuxia Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Zhen Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
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31
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Huang Z, Zhu D, Wu L, He M, Zhou X, Zhang L, Zhang H, Wang W, Zhu J, Cheng W, Chen Y, Fan Y, Qi L, Yin Y, Zhu W, Shu Y, Liu P. Six Serum-Based miRNAs as Potential Diagnostic Biomarkers for Gastric Cancer. Cancer Epidemiol Biomarkers Prev 2017; 26:188-196. [PMID: 27756776 DOI: 10.1158/1055-9965.epi-16-0607] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/15/2016] [Accepted: 09/21/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Circulating miRNAs in serum may serve as promising diagnostic biomarkers for patients with gastric cancer. METHODS Using qRT-PCR-based Exiqon panel, we identified 58 differentially expressed miRNAs from three gastric cancer pool samples and one normal control (NC) pool in the initial screening phase. Identified miRNAs were further validated in the training (49 gastric cancer vs. 47 NCs) and validation phases (154 gastric cancer vs. 120 NCs) using qRT-PCR. The expression levels of the miRNAs were also determined in tissues, arterial serum, and exosomes. RESULTS Consequently, six serum miRNAs (miR10b-5p, miR132-3p, miR185-5p, miR195-5p, miR-20a3p, and miR296-5p) were significantly overexpressed in gastric cancer compared with NCs. The areas under the receiver operating characteristic curve of the six-miRNA panel were 0.764 and 0.702 for the training and validation phases, respectively. miR10b-5p and miR296-5p were significantly upregulated in gastric cancer tissues (n = 188). In addition, patients who did not receive adjuvant chemotherapy with high expression of miR10b-5p or miR296-5p in tissues tended to suffer worse overall survival. Furthermore, the expression levels of miR10b-5p, miR195-5p, miR20a-3p, and miR296-5p were significantly elevated in exosomes from gastric cancer serum samples (n = 30). CONCLUSIONS We identified a six-miRNA panel in serum for the detection of gastric cancer. IMPACT Our findings provide a novel serum miRNA signature for gastric cancer diagnosis, and will serve as the basis of the application of circulating miRNAs in clinical for the detection of gastric cancer in the future. Cancer Epidemiol Biomarkers Prev; 26(2); 188-96. ©2016 AACR.
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Affiliation(s)
- Zebo Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Danxia Zhu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Lirong Wu
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing, China
| | - Mingfeng He
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Zhou
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lan Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huo Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Wang
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Zhu
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing, China
| | - Wenfang Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Chen
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Fan
- State Key Laboratory of Natural Medicines and Department of Pharmacognosy, China Pharmaceutical University, Nanjing, China
| | - Lianwen Qi
- State Key Laboratory of Natural Medicines and Department of Pharmacognosy, China Pharmaceutical University, Nanjing, China
| | - Yin Yin
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Cancer Center of Nanjing Medical University, Nanjing, China
| | - Ping Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Cancer Center of Nanjing Medical University, Nanjing, China
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32
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Zou Q, Wu H, Fu F, Yi W, Pei L, Zhou M. RKIP suppresses the proliferation and metastasis of breast cancer cell lines through up-regulation of miR-185 targeting HMGA2. Arch Biochem Biophys 2016; 610:25-32. [DOI: 10.1016/j.abb.2016.09.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 09/08/2016] [Accepted: 09/17/2016] [Indexed: 01/30/2023]
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Bibi F, Naseer MI, Alvi SA, Yasir M, Jiman-Fatani AA, Sawan A, Abuzenadah AM, Al-Qahtani MH, Azhar EI. microRNA analysis of gastric cancer patients from Saudi Arabian population. BMC Genomics 2016; 17:751. [PMID: 27766962 PMCID: PMC5073958 DOI: 10.1186/s12864-016-3090-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background The role of small non-coding microRNAs (miRNAs) in several types of cancer has been evident. However, its expression studies have never been performed in gastric cancer (GC) patients from Saudi population. First time this study was conducted to identify miRNAs that are differentially expressed in GC patients compared with normal controls. Methods We investigated the role of miRNAs in GC patients using formalin-fixed paraffin-embedded (FFPE) tissues of 34 samples from GC patients (early stage = 7 and late-stage = 26) and 15 from normal control. We have used miRNA microarray analysis and validated the results by Real-time quantitative PCR (RT-qPCR). Results We obtained data of 1082 expressed genes, from cancer tissues and noncancerous tissues (49 samples in total). Where 129 genes were up-regulated (P > 0.05) and 953 genes (P > 0.05) were down-regulated in 49 FFPE tissue samples. Only 33 miRNAs had significant expression in early and late-stage cancer tissues. After candidate miRNAs were selected, RT-qPCR further confirmed that four miRNAs (hsa-miR-200c-3p, hsa-miR-3613, hsa-miR-27b-3p, hsa-miR-4668-5p) were significantly aberrant in GC tissues compared to the normal gastric tissues. Conclusions In this study we provide miRNAs profile of GC where many miRNAs showed aberrant expression from normal tissues, suggesting their involvement in the development and progression of gastric cancer. In early and late-stage miR-200c-3p showed significant down regulation as compare to control samples. Many of miRNAs reported in our study showing up-regulation are new and not reported before may be due to population difference. In conclusion, our results suggest that miR-200c-3p had potential to use as diagnostic biomarker for distinguishing GC patients from normal individuals and can be used for diagnosis of cancer at early stage.
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Affiliation(s)
- Fehmida Bibi
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.
| | - Muhammad I Naseer
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Sana Akhtar Alvi
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia
| | - Muhammad Yasir
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia
| | - Asif A Jiman-Fatani
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali Sawan
- Department of Anatomical Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adel M Abuzenadah
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.,KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia
| | - Mohammed H Al-Qahtani
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Esam I Azhar
- Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH, Lin KH. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int J Mol Sci 2016; 17:945. [PMID: 27322246 PMCID: PMC4926478 DOI: 10.3390/ijms17060945] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022] Open
Abstract
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Wei Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Pei-Hsuan Lu
- Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
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35
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Treece AL, Duncan DL, Tang W, Elmore S, Morgan DR, Dominguez RL, Speck O, Meyers MO, Gulley ML. Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns. J Transl Med 2016; 96:661-71. [PMID: 26950485 PMCID: PMC5767475 DOI: 10.1038/labinvest.2016.33] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 12/09/2015] [Accepted: 01/12/2016] [Indexed: 12/27/2022] Open
Abstract
MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/virology
- Aged
- Aged, 80 and over
- Case-Control Studies
- Epstein-Barr Virus Infections/genetics
- Epstein-Barr Virus Infections/metabolism
- Epstein-Barr Virus Infections/virology
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Humans
- Male
- MicroRNAs/blood
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Middle Aged
- Pilot Projects
- RNA, Neoplasm/blood
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- RNA, Viral/blood
- RNA, Viral/genetics
- RNA, Viral/metabolism
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/virology
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Affiliation(s)
- Amanda L Treece
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Daniel L Duncan
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Weihua Tang
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sandra Elmore
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Douglas R Morgan
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Ricardo L Dominguez
- Department of Gastroenterology, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Olga Speck
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael O Meyers
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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36
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Jiang CY, Ruan Y, Wang XH, Zhao W, Jiang Q, Jing YF, Han BM, Xia SJ, Zhao FJ. MiR-185 attenuates androgen receptor function in prostate cancer indirectly by targeting bromodomain containing 8 isoform 2, an androgen receptor co-activator. Mol Cell Endocrinol 2016; 427:13-20. [PMID: 26940039 DOI: 10.1016/j.mce.2016.02.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 02/27/2016] [Accepted: 02/28/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Aberrant androgen receptor (AR) signaling functions are implicated in prostate cancer (PCa) pathogenesis. Here, we studied interactions between miR-185 and the bromodomain containing 8 isoform 2 (BRD8 ISO2) to investigate indirect mechanisms of miR-185 with respect to AR function through BRD8 ISO2 in PCa. METHODS Putative miRNA response element (MRE) of miR-185 in 3'-untranslated region (3'-UTR) of BRD8 ISO2 mRNA was predicted by software and confirmed using dual-luciferase assays and Ago2 immunoprecipitation. BRD8 and AR expression were determined by qRT-PCR and Western blot in PCa cells and tissues. MMTV-Fluc reporter plasmids and dual-luciferase assays were used to evaluate AR activity. RESULTS MRE prediction, dual-luciferase assays and Ago2 immunoprecipitation confirmed that miR-185 is capable of binding the 3'-UTR of BRD8 ISO2 mRNA. QRT-PCR and Western blot indicated that BRD8 ISO2 expression is decreased by miR-185 mimic transfection while increased by miR-185 inhibitor transfection. MMTV-Fluc reporter assays revealed that miR-185 can attenuate AR function by suppressing BRD8 ISO2. Additionally, Pearson's correlation analyses confirmed that BRD8 ISO2 mRNA expression is inversely correlated with miR-185 expression in clinical specimens. CONCLUSION In addition to suppression of AR expression, miR-185 can attenuate AR function indirectly by suppressing BRD8 ISO2. MiR-185 and BRD8 ISO2 may be possible therapeutic targets for PCa treatment.
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Affiliation(s)
- Chen-Yi Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yuan Ruan
- Department of Urology, Shanghai General Hospital Affiliated to Nanjing Medical University, Shanghai 200080, China
| | - Xiao-Hai Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Wei Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qi Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yi-Feng Jing
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Bang-Min Han
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Shu-Jie Xia
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Urology, Shanghai General Hospital Affiliated to Nanjing Medical University, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China.
| | - Fu-Jun Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China.
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37
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Kim EK, Choi EJ, Debnath T. Role of phytochemicals in the inhibition of epithelial–mesenchymal transition in cancer metastasis. Food Funct 2016; 7:3677-85. [DOI: 10.1039/c6fo00901h] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epithelial–mesenchymal transition (EMT) development is controlled by several signaling pathways including Hedgehog, Wnt, fibroblast growth factors (FGF), hepatocyte growth factor/scatter factor (HGF),etc. Phytochemicals is very promising therapeutic candidate that inhibit the progression of EMT by inhibiting the signaling pathways.
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Affiliation(s)
- Eun-Kyung Kim
- Division of Food BioScience
- College of Biomedical and Health Sciences
- Konkuk University
- Chungju 27478
- Republic of Korea
| | - Eun-Ju Choi
- Division of Sport Science
- College of Science and Technology
- Konkuk University
- Chungju 27478
- Republic of Korea
| | - Trishna Debnath
- Department of Food Science and Biotechnology
- Dongguk University
- Goyang 10326
- Republic of Korea
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38
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Yu X, Li Z, Chan MTV, Wu WKK. The roles of microRNAs in Wilms' tumors. Tumour Biol 2015; 37:1445-50. [PMID: 26634744 DOI: 10.1007/s13277-015-4514-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 11/25/2015] [Indexed: 12/12/2022] Open
Abstract
Wilms' tumor is the most common renal tumor in children in which diffusely anaplastic or unfavorable histology foreshadows poor prognosis. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating evidence shows that microRNA dysregulation takes part in the pathogenesis of many renal diseases, such as chronic kidney diseases, polycystic kidney disease, renal fibrosis, and renal cancers. In Wilms' tumor, dysregulation of some key oncogenic or tumor-suppressing microRNAs, such as miR-17~92 cluster, miR-185, miR-204, and miR-483, has been documented. In this review, we will summarize current evidence on the role of dysregulated microRNAs in the development of Wilms' tumor.
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Affiliation(s)
- Xin Yu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100042, China
| | - Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100042, China.
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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39
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Mahmood S, Bhatti A, Syed NA, John P. The microRNA regulatory network: a far-reaching approach to the regulate the Wnt signaling pathway in number of diseases. J Recept Signal Transduct Res 2015; 36:310-8. [PMID: 26523375 DOI: 10.3109/10799893.2015.1080273] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Wnt signaling pathway plays an important role in cell renewal, tumorigenesis, organogenesis, bone formation and bone resorption. Wnt signaling pathway is divided into two outlets: Wnt-β-catenin pathway (canonical pathway) and Wnt-calcium pathway (non-canonical pathway). miRNAs play a key role in the regulation of Wnt signaling pathway. In this review, we highlight the basic indulgent of miRNAs-mediated regulation of Wnt signaling pathway. We focus on the role of miRNAs at different levels of Wnt signaling: signaling molecules, their associated signaling proteins, regulatory proteins, transcription factors and related cytokines. Finally, we concluded that these multiple levels of targeting may have diagnostic potential as well as therapeutic prospective in future treatment.
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Affiliation(s)
- Shahid Mahmood
- a Immunogenetic Lab, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST) , Islamabad , Pakistan
| | - Attya Bhatti
- a Immunogenetic Lab, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST) , Islamabad , Pakistan
| | - Nida Ali Syed
- a Immunogenetic Lab, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST) , Islamabad , Pakistan
| | - Peter John
- a Immunogenetic Lab, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST) , Islamabad , Pakistan
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40
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Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6:111-132. [PMID: 26468448 PMCID: PMC4600186 DOI: 10.5306/wjco.v6.i5.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/22/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
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miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2015; 2015:365273. [PMID: 26504803 PMCID: PMC4609369 DOI: 10.1155/2015/365273] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 05/08/2015] [Accepted: 05/18/2015] [Indexed: 12/01/2022]
Abstract
Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.
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42
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Kanda M, Kodera Y. Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol 2015; 21:9838-9852. [PMID: 26379391 PMCID: PMC4566379 DOI: 10.3748/wjg.v21.i34.9838] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/15/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the third most common cause of cancer-related death in the world, representing a major global health issue. Although the incidence of GC is declining, the outcomes for GC patients remain dismal because of the lack of effective biomarkers to detect early GC and predict both recurrence and chemosensitivity. Current tumor markers for GC, including serum carcinoembryonic antigen and carbohydrate antigen 19-9, are not ideal due to their relatively low sensitivity and specificity. Recent improvements in molecular techniques are better able to identify aberrant expression of GC-related molecules, including oncogenes, tumor suppressor genes, microRNAs and long non-coding RNAs, and DNA methylation, as novel molecular markers, although the molecular pathogenesis of GC is complicated by tumor heterogeneity. Detection of genetic and epigenetic alterations from gastric tissue or blood samples has diagnostic value in the management of GC. There are high expectations for molecular markers that can be used as new screening tools for early detection of GC as well as for patient stratification towards personalized treatment of GC through prediction of prognosis and drug-sensitivity. In this review, the studies of potential molecular biomarkers for GC that have been reported in the publicly available literature between 2012 and 2015 are reviewed and summarized, and certain highlighted papers are examined.
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43
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Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. Sci Rep 2015; 5:11251. [PMID: 26059512 PMCID: PMC4462022 DOI: 10.1038/srep11251] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 05/05/2015] [Indexed: 12/14/2022] Open
Abstract
The differential expression of microRNAs (miRNAs) in plasma of gastric cancer (GC) patients may serve as a diagnostic biomarker. A total of 33 miRNAs were identified through the initial screening phase (3 GC pools vs. 1 normal control (NC) pool) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel (miRCURY-Ready-to-Use-PCR-Human-panel-I + II-V1.M). By qRT-PCR, these miRNAs were further assessed in training (30 GC VS. 30 NCs) and testing stages (71 GC VS. 61 NCs). We discovered a plasma miRNA signature including five up-regulated miRNAs (miR-185, miR-20a, miR-210, miR-25 and miR-92b), and this signature was evaluated to be a potential diagnostic marker of GC. The areas under the receiver operating characteristic curve of the signature were 0.86, 0.74 and 0.87 for the training, testing and the external validation stages (32 GC VS. 18 NCs), respectively. The five miRNAs were consistently dysregulated in GC tissues (n = 30). Moreover, miR-185 was decreased while miR-20a, miR-210 and miR-92b were increased in arterial plasma (n = 38). However, none of the miRNAs in the exosomes showed different expression between 10 GC patients and 10 NCs. In conclusion, we identified a five-miRNA signature in the peripheral plasma which could serve as a non-invasive biomarker in detection of GC.
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44
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Saito T, Kurashige J, Nambara S, Komatsu H, Hirata H, Ueda M, Sakimura S, Uchi R, Takano Y, Shinden Y, Iguchi T, Eguchi H, Ehata S, Murakami K, Sugimachi K, Mimori K. A Long Non-coding RNA Activated by Transforming Growth Factor-β is an Independent Prognostic Marker of Gastric Cancer. Ann Surg Oncol 2015; 22 Suppl 3:S915-22. [PMID: 25986864 DOI: 10.1245/s10434-015-4554-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND A recent study reported that long non-coding RNA activated by TGF-β (lncRNA-ATB) induced epithelial-mesenchymal transition (EMT) through the transforming growth factor-β (TGF-β)/miR-200s/ZEB axis in hepatocellular carcinoma. Herein, we focused on the clinical significance of lncRNA-ATB in gastric cancer (GC) patients. MATERIALS AND METHODS Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to examine expression of lncRNA-ATB, miR-200b, and miR-200c in GC tissues (n = 183). Patients were divided into high and low lncRNA-ATB expression groups using a cutoff of lncRNA-ATB/GAPDH ≥0.60 or <0.60 to determine the clinicopathological significance of lncRNA-ATB in GC. Moreover, we evaluated the expression of TGF-β, lncRNA-ATB, miR-200s, and ZEB1 in GC cell lines by qRT-PCR. GC cell lines were treated by recombinant TGF-β1 or TGF-β receptor inhibitor to examine morphologic changes and genetic alterations, such as lncRNA-ATB, miR-200s, and ZEB1 levels, with respect to the EMT phenotype. RESULTS The high lncRNA-ATB group experienced a lower overall survival rate compared with the low lncRNA-ATB group, and multivariate analysis indicated that lncRNA-ATB was an independent prognostic factor (hazard ratio 3.50; 95 % CI 1.73-7.44; p = 0.0004). miR-200c levels were lower and ZEB1 levels were higher in the high lncRNA-ATB group than in the low lncRNA-ATB group. Treatment with TGF-β in GC cell lines resulted in morphological EMT changes, upregulation of lncRNA-ATB and ZEB1, and downregulation of miR-200c and CDH1. SB431542 reduced lncRNA-ATB expression. CONCLUSION LncRNA-ATB plays an important role in EMT to promote invasion and metastasis through the TGF-β/miR-200s/ZEB axis, resulting in a poor prognosis in GC. LncRNA-ATB is a novel biomarker of lncRNA, indicative of a poor prognosis in GC patients.
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Affiliation(s)
- Tomoko Saito
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.,Department of Gastroenterology, Oita University Hospital, Yufu, Japan
| | - Junji Kurashige
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Sho Nambara
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hisateru Komatsu
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hidenari Hirata
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Masami Ueda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Shotaro Sakimura
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Ryutaro Uchi
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Yuki Takano
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Yoshiaki Shinden
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Tomohiro Iguchi
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hidetoshi Eguchi
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Shogo Ehata
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University Hospital, Yufu, Japan
| | - Keishi Sugimachi
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
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Mu YP, Sun WJ, Lu CW, Su XL. MicroRNAs May Serve as Emerging Molecular Biomarkers for Diagnosis and Prognostic Assessment or as Targets for Therapy in Gastric Cancer. Asian Pac J Cancer Prev 2015; 16:4813-4820. [PMID: 26163596 DOI: 10.7314/apjcp.2015.16.12.4813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia countries. Most GC patients have been reported with low early diagnosis rate and show extremely poor prognosis. Therefore, it is necessary to develop novel and more sensitive biomarkers to improve early diagnosis and therapy in order to provide longer survival and better quality of life for gastric cancer patients. MicroRNAs (miRNAs) play crucial roles in GC development and progression. miRNAs have emerged as a novel molecular biomarker for cancer diagnosis, prognosis and therapy with surprising stability in tissues, serum or other body fluids. This review summarizes major advances in our current knowledge about potential miRNA biomarkers for GC that have been reported in the past two years.
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Affiliation(s)
- Yong-Ping Mu
- Department of Clinical Laboratory Center, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China E-mail : ;
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STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer. Oncogene 2014; 34:4808-20. [PMID: 25531324 PMCID: PMC4569941 DOI: 10.1038/onc.2014.404] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 10/21/2014] [Accepted: 11/04/2014] [Indexed: 01/01/2023]
Abstract
STIM1 (stromal interaction molecule 1), an endoplasmic reticulum Ca2+ sensor that triggers the store-operated Ca2+ entry activation, has recently been implicated in cancer progression. However, the role of STIM1 in the progression and metastasis of colorectal cancer (CRC) has not been addressed. In this study, we confirmed increased expression of STIM1 in highly invasive CRC cell lines. Enhanced expression of STIM1 promoted CRC cell metastasis in vitro and in vivo, whereas silencing of STIM1 with small interfering RNA resulted in reduced metastasis. Ectopic expression of STIM1 in CRC cells induced epithelial-to-mesenchymal transition (EMT), whereas silencing of STIM1 had the opposite effect. Furthermore, STIM1 expression was markedly higher in CRC tissues than in adjacent noncancerous tissues. STIM1 overexpression correlated with poor differentiation and higher tumor node metastasis stage. CRC patients with positive STIM1 expression had poorer prognoses than those with negative STIM1 expression. Moreover, STIM1 was found to be a direct target of miR-185, a microRNA (miRNA) that has not previously been reported to be involved in EMT, in both CRC tissues and cell lines. Taken together, these findings demonstrate for the first time that STIM1 promotes metastasis and is associated with cancer progression and poor prognosis in patients with CRC. In addition, we show that expression of STIM1 is regulated by a posttranscriptional regulatory mechanism mediated by a new EMT-related miRNA. This novel miR-185–STIM1 axis promotes CRC metastasis and may be a candidate biomarker for prognosis and a target for new therapies.
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Research on the efficacy of Celastrus Orbiculatus in suppressing TGF-β1-induced epithelial-mesenchymal transition by inhibiting HSP27 and TNF-α-induced NF-κ B/Snail signaling pathway in human gastric adenocarcinoma. Altern Ther Health Med 2014; 14:433. [PMID: 25370696 PMCID: PMC4232669 DOI: 10.1186/1472-6882-14-433] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 10/27/2014] [Indexed: 01/13/2023]
Abstract
BACKGROUND Celastrus orbiculatus has been used as a folk medicine in China for the treatment of many diseases. In the laboratory, the ethyl acetate extract of Celastrus orbiculatus (COE) displays a wide range of anticancer functions. However, the inhibition of the metastasis mechanism of COE in gastric cancer cells has not been investigated so far. METHODS The present study was undertaken to determine if the anti-metastasis effect of COE was involved in inhibiting of epithelial-mesenchymal transition (EMT) of human gastric adenocarcinoma SGC-7901 cells. In vitro, a well-established experimental EMT model involving transforming growth factor β1 (TGF-β1) was applied. Viability, invasion and migration, protein and mRNA expression of tumor cells were analyzed by MTT assay, transwell assay, western blot and real-time PCR, respectively. The molecular targets of COE in SGC-7901 cells were investigated by two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF mass spectrometer. Overexpression of heat shock protein 27 (HSP27) was performed by transfected with the recombinant retroviral expression plasmid. In vivo, the anti-metastasis mechanisms of COE in the peritoneal gastric cancer xenograft model was explored and the effect was tested. RESULTS The non-cytostatic concentrations of COE effectively inhibited TGF-β1 induced EMT process in SGC-7901 cells, which is characterized by prevented morphological changes, increased E-cadherin expression and decreased Vimentin, N-cadherin expression. Moreover, COE inhibited invasion and migration induced by TGF-β1. Using a comparative proteomics approach, four proteins were identified as differently expressed, with HSP27 protein being one of the most significantly down-regulated proteins induced by COE. Moreover, the activation of nuclear factor κB (NF-κB)/Snail signaling pathway induced by tumor necrosis factor-α (TNF-α) was also attenuated under the pretreatment of COE. Interestingly, overexpression of HSP27 significantly decreases the inhibitory effect of COE on EMT and the NF-κB/Snail pathway. Furthermore, COE significantly reduced the number of peritoneal metastatic nodules in the peritoneal gastric cancer xenograft model. CONCLUSIONS Taken together, these results suggest that COE inhibits the EMT by suppressing the expression of HSP27, correlating with inhibition of NF-κB/Snail signal pathways in SGC-7901 cells. Based on these results, COE may be considered a novel anti-cancer agent for the treatment of metastasis in gastric cancer.
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Tang H, Liu P, Yang L, Xie X, Ye F, Wu M, Liu X, Chen B, Zhang L, Xie X. miR-185 Suppresses Tumor Proliferation by Directly Targeting E2F6 and DNMT1 and Indirectly Upregulating BRCA1 in Triple-Negative Breast Cancer. Mol Cancer Ther 2014; 13:3185-97. [DOI: 10.1158/1535-7163.mct-14-0243] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Lai H, Jin Q, Lin Y, Mo X, Li B, He K, Chen J. Combined use of lysyl oxidase, carcino-embryonic antigen, and carbohydrate antigens improves the sensitivity of biomarkers in predicting lymph node metastasis and peritoneal metastasis in gastric cancer. Tumour Biol 2014; 35:10547-10554. [PMID: 25060181 PMCID: PMC4213369 DOI: 10.1007/s13277-014-2355-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 07/14/2014] [Indexed: 12/21/2022] Open
Abstract
The purpose of this study was to determine whether lysyl oxidase (LOX) is a useful marker of metastasis in gastric cancer (GC) patients in combination with tumor markers carcino-embryonic antigen (CEA), carbohydrate antigen 724 (CA724), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125). There were 215 GC patients (67 without metastasis, 102 with lymph node metastasis, and 46 with peritoneal metastasis) who presented to the Affiliated Cancer Hospital of Guangxi Medical University between May 2009 and November 2012 that were enrolled in this study. The LOX expression level and the serum concentration of the four tumor markers were evaluated preoperatively. All patients underwent computed tomography (CT) and ultrasonography (US) before surgery. Statistical analysis, including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC) analysis, and logistic regression analysis, was performed to evaluate the diagnostic value of these markers in predicting metastasis in GC. For predicting lymph node metastasis in GC, the sensitivity of LOX, CEA, CA724, CA199, and CA125 was 44.12, 12.75, 21.57, 23.53, and 15.69 %, respectively, and increased to 79.41 % in combination. For predicting peritoneal metastasis in GC, the sensitivity of these markers was 56.52, 23.91, 34.78, 36.96, and 34.78 %, respectively, and increased to 91.30 % in combination. Combining LOX with CEA, CA724, CA199, and CA125 could increase the sensitivity of predicting lymph nodes metastasis and peritoneal metastasis in GC. Surgeons can use these markers to determine the best treatment options for patients. Additional large-scale, prospective, multicenter studies are urgently needed to further confirm the results of this study.
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Affiliation(s)
- Hao Lai
- Graduate College, Guangxi Medical University, Nanning, 530021 Guangxi Autonomous Region China
| | - Qinwen Jin
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021 Guangxi Autonomous Region China
| | - Yuan Lin
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021 Guangxi Autonomous Region China
| | - Xianwei Mo
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021 Guangxi Autonomous Region China
| | - Bo Li
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021 Guangxi Autonomous Region China
| | - Ke He
- Department of Head and Neck Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Autonomous Region China
| | - Jiansi Chen
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021 Guangxi Autonomous Region China
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Kim Y, Kim H, Park H, Park D, Lee H, Lee YS, Choe J, Kim YM, Jeoung D. miR-326-histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs. J Biol Chem 2014; 289:28019-39. [PMID: 25138213 DOI: 10.1074/jbc.m114.578229] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs in vitro and in vivo. TargetScan analysis predicted miR-326 as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and miR-326. miR-326 decreased the apoptotic effect of anti-cancer drugs, and the miR-326 inhibitor increased the apoptotic effect of anti-cancer drugs. miR-326 enhanced the invasion and migration potential of cancer cells. The miR-326 inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as miR-200b, miR-217, and miR-335. miR-200b, miR-217, and miR-335 negatively regulated the expression of miR-326 and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted miR-200b and miR-217 as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and miR-326 acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.
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Affiliation(s)
| | - Hyuna Kim
- From the Departments of Biochemistry and
| | | | | | - Hansoo Lee
- Biological Sciences, College of Natural Sciences, and
| | - Yun Sil Lee
- the College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
| | - Jongseon Choe
- Graduate School of Medicine, Kangwon National University, Chunchon 200-701 and
| | - Young Myeong Kim
- Graduate School of Medicine, Kangwon National University, Chunchon 200-701 and
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