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Xiong T, Wang D, Yang H, Liu B, Li Y, Yu W, Wang J, She Q. miR-194-3p regulates epithelial-mesenchymal transition in embryonic epicardial cells via p120/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024; 56:717-729. [PMID: 38676398 PMCID: PMC11381220 DOI: 10.3724/abbs.2024051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024] Open
Abstract
The epicardium is integral to cardiac development and facilitates endogenous heart regeneration and repair. While miR-194-3p is associated with cellular migration and invasion, its impact on epicardial cells remains uncharted. In this work we use gain-of-function and loss-of-function methodologies to investigate the function of miR-194-3p in cardiac development. We culture embryonic epicardial cells in vitro and subject them to transforming growth factor β (TGF-β) treatment to induce epithelial-mesenchymal transition (EMT) and monitor miR-194-3p expression. In addition, the effects of miR-194-3p mimics and inhibitors on epicardial cell development and changes in EMT are investigated. To validate the binding targets of miR-194-3p and its ability to recover the target gene-phenotype, we produce a mutant vector p120-catenin-3'UTR-MUT. In epicardial cells, TGF-β-induced EMT results in a notable overexpression of miR-194-3p. The administration of miR-194-3p mimics promotes EMT, which is correlated with elevated levels of mesenchymal markers. Conversely, miR-194-3p inhibitor attenuates EMT. Further investigations reveal a negative correlation between miR-194-3p and p120-catenin, which influences β-catenin level in the cell adhesion pathway. The suppression of EMT caused by the miR-194-3p inhibitor is balanced by silencing of p120-catenin. In conclusion, miR-194-3p directly targets p120-catenin and modulates its expression, which in turn alters β-catenin expression, critically influencing the EMT process in the embryonic epicardial cells via the cell adhesion mechanism.
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Wei QY, Jin F, Wang ZY, Li BJ, Cao WB, Sun ZY, Mo SJ. MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:1497-1523. [PMID: 38617454 PMCID: PMC11008420 DOI: 10.3748/wjg.v30.i11.1497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/12/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Affiliation(s)
- Qi-Ying Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Feng Jin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhong-Yu Wang
- Department of Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing-Jie Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Wen-Bo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhi-Yan Sun
- Division of Special Service, Department of Basic Oncology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sai-Jun Mo
- Department of Basic Science of Oncology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Taheri F, Ebrahimi SO, Heidari R, Pour SN, Reiisi S. Mechanism and function of miR-140 in human cancers: A review and in silico study. Pathol Res Pract 2023; 241:154265. [PMID: 36509008 DOI: 10.1016/j.prp.2022.154265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022]
Abstract
MicroRNA-140 (miR-140) acts as a tumor suppressor and plays a vital role in cell biological functions such as cell proliferation, apoptosis, and DNA repair. The expression of this miRNA has been shown to be considerably decreased in cancer tissues and cell lines compared with normal adjacent tissues. Consequently, aberrant expression of some miR-140 target genes can lead to the initiation and progression of various human cancers, such as breast cancer, gastrointestinal cancers, lung cancer, and prostate cancer. The dysregulation of the miR-140 network also affects cell proliferation, invasion, metastasis, and apoptosis of cancer cells by affecting various signaling pathways. Besides, up-regulation of miR-140 could enhance the efficacy of chemotherapeutic agents in different cancer. We aimed to cover most aspects of miR-140 function in cancer development and address its importance in different stages of cancer progression.
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Affiliation(s)
- Forough Taheri
- Department of Genetics, Sharekord Branch, Islamic Azad University, Sharekord, Iran
| | - Seyed Omar Ebrahimi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Razieh Heidari
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Somaye Nezamabadi Pour
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Somayeh Reiisi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran.
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Mousavi SM, Derakhshan M, Baharloii F, Dashti F, Mirazimi SMA, Mahjoubin-Tehran M, Hosseindoost S, Goleij P, Rahimian N, Hamblin MR, Mirzaei H. Non-coding RNAs and glioblastoma: Insight into their roles in metastasis. Mol Ther Oncolytics 2022; 24:262-287. [PMID: 35071748 PMCID: PMC8762369 DOI: 10.1016/j.omto.2021.12.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Glioma, also known as glioblastoma multiforme (GBM), is the most prevalent and most lethal primary brain tumor in adults. Gliomas are highly invasive tumors with the highest death rate among all primary brain malignancies. Metastasis occurs as the tumor cells spread from the site of origin to another site in the brain. Metastasis is a multifactorial process, which depends on alterations in metabolism, genetic mutations, and the cancer microenvironment. During recent years, the scientific study of non-coding RNAs (ncRNAs) has led to new insight into the molecular mechanisms involved in glioma. Many studies have reported that ncRNAs play major roles in many biological procedures connected with the development and progression of glioma. Long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are all types of ncRNAs, which are commonly dysregulated in GBM. Dysregulation of ncRNAs can facilitate the invasion and metastasis of glioma. The present review highlights some ncRNAs that have been associated with metastasis in GBM. miRNAs, circRNAs, and lncRNAs are discussed in detail with respect to their relevant signaling pathways involved in metastasis.
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Affiliation(s)
- Seyed Mojtaba Mousavi
- Department of Neurosciences and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Derakhshan
- Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatereh Baharloii
- Department of Cardiology, Chamran Cardiovascular Research Education Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saereh Hosseindoost
- Brain and Spinal Cord Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouya Goleij
- Department of Genetics, Faculty of Biology, Sana Institute of Higher Education, Sari, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Liu XS, Gao Y, Wu LB, Wan HB, Yan P, Jin Y, Guo SB, Wang YL, Chen XQ, Zhou LM, Yang JW, Kui XY, Liu XY, Pei ZJ. Comprehensive Analysis of GLUT1 Immune Infiltrates and ceRNA Network in Human Esophageal Carcinoma. Front Oncol 2021; 11:665388. [PMID: 34123828 PMCID: PMC8195627 DOI: 10.3389/fonc.2021.665388] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/05/2021] [Indexed: 12/11/2022] Open
Abstract
Background Glucose transporter 1 (GLUT1) is encoded by the solute carrier family 2A1 (SLC2A1) gene and is one of the glucose transporters with the greatest affinity for glucose. Abnormal expression of GLUT1 is associated with a variety of cancers. However, the biological role of GLUT1 in esophageal carcinoma (ESCA) remains to be determined. Methods We analyzed the expression of GLUT1 in pan-cancer and ESCA as well as clinicopathological analysis through multiple databases. Use R and STRING to perform GO/KEGG function enrichment and PPI analysis for GLUT1 co-expression. TIMER and CIBERSORT were used to analyze the relationship between GLUT1 expression and immune infiltration in ESCA. The TCGA ESCA cohort was used to analyze the relationship between GLUT1 expression and m6A modification in ESCA, and to construct a regulatory network in line with the ceRNA hypothesis. Results GLUT1 is highly expressed in a variety of tumors including ESCA, and is closely related to histological types and histological grade. GO/KEGG functional enrichment analysis revealed that GLUT1 is closely related to structural constituent of cytoskeleton, intermediate filament binding, cell-cell adheres junction, epidermis development, and P53 signaling pathway. PPI shows that GLUT1 is closely related to TP53, GIPC1 and INS, and these three proteins all play an important role in tumor proliferation. CIBERSORT analysis showed that GLUT1 expression is related to the infiltration of multiple immune cells. When GLUT1 is highly expressed, the number of memory B cells decreases. ESCA cohort analysis found that GLUT1 expression was related to 7 m6A modifier genes. Six possible crRNA networks in ESCA were constructed by correlation analysis, and all these ceRNA networks contained GLUT1. Conclusion GLUT1 can be used as a biomarker for the diagnosis and treatment of ESCA, and is related to tumor immune infiltration, m6A modification and ceRNA network.
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Affiliation(s)
- Xu-Sheng Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Li-Bing Wu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hua-Bing Wan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Peng Yan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yang Jin
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Shi-Bo Guo
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ya-Lan Wang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | | | - Lu-Meng Zhou
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jian-Wei Yang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xue-Yan Kui
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiao-Yu Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhi-Jun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, China
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Effects of miRNA-140 on the Growth and Clinical Prognosis of SMMC-7721 Hepatocellular Carcinoma Cell Line. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6638915. [PMID: 33628799 PMCID: PMC7884124 DOI: 10.1155/2021/6638915] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/27/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
Background A growing number of studies have suggested that microRNAs exert an essential role in the development and occurrence of multiple tumours and act as crucial regulators in various biological processes. However, the expression and function of miRNA-140 in hepatocellular carcinoma (HCC) cells are not yet adequately identified and manifested. Methods The expression of miRNA-140 was determined in HCC tissues and adjacent nontumour tissues by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis and Cox regression analysis were performed to explore the correlation between miRNA-140 expression level and the survival rate of patients with HCC. Additionally, overexpression experiments were conducted to investigate the biological role of miRNA-140 in HCC cells. Bioinformatics was used to predict the related target genes and pathways of miRNA-140. Results QRT-PCR results signified that the expression level of miRNA-140 in HCC was lower than that of adjacent normal tissues (P < 0.0001). Compared with the control group, the SMMC-7721 HCC cells in the miRNA-140 mimic group had a decrease in proliferation, migration, and invasion (P < 0.05), whereas those in the miRNA-140 inhibitor group had an increase in proliferation, migration, and invasion (P < 0.05). Cell cycle arrest occurred in the G0/1 phase. Prognosis analysis showed that the expression level of miRNA-140 was not related to the prognosis of HCC. Furthermore, the Kaplan-Meier test revealed that patients with lower miRNA-140 expression levels in liver cancer tissue had significantly shorter disease-free survival (DFS, P = 0.004) and overall survival (OS) times (P = 0.010) after hepatectomy. Cox regression analysis further indicated that miRNA-140 was an independent risk factor that may affect the DFS (P = 0.004) and OS times (P = 0.014) of patients after hepatectomy. Our results suggested that miRNA-140 might be a crucial regulator involved in the HCC progression and is thus considered a potential prognostic biomarker and therapeutic target for HCC.
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Wang Y, Chen J, Wang X, Wang K. miR-140-3p inhibits bladder cancer cell proliferation and invasion by targeting FOXQ1. Aging (Albany NY) 2020; 12:20366-20379. [PMID: 33098639 PMCID: PMC7655201 DOI: 10.18632/aging.103828] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
Upregulation of the forkhead box protein Q1 (FOXQ1) promotes bladder cancer (BCa) cell growth and metastasis. Factors affecting FOXQ1 expression at the post-transcriptional level have not yet been identified. We performed cell proliferation, cell invasion, and tumorigenesis experiments to characterize the relationship between FOXQ1 and miR-140-3p. We found that FOXQ1 was significantly upregulated and miR-140-3p was significantly downregulated in BCa tissues. We also identified an inverse correlation between miR-140-3p and FOXQ1 expression in BCa tissues. Overexpression of miR-140-3p reduced FOXQ1 expression, suppressing BCa cell proliferation and invasion. A luciferase assay confirmed that miR-140-3p bound to the 3’-UTR of FOXQ1 mRNA and decreased its expression. In addition, we used a mouse xenograft model to demonstrate that miR-140-3p suppressed tumor cell growth in vivo. Our findings suggest that miR-140-3p suppresses BCa cell proliferation and invasion by directly decreasing FOXQ1 expression.
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Affiliation(s)
- Yuan Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Junwen Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Yang S, Li X, Shen W, Hu H, Li C, Han G. MicroRNA-140 Represses Esophageal Cancer Progression via Targeting ZEB2 to Regulate Wnt/β-Catenin Pathway. J Surg Res 2020; 257:267-277. [PMID: 32862055 DOI: 10.1016/j.jss.2020.07.074] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 06/11/2020] [Accepted: 07/11/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND MicroRNAs have been reported to play regulatory functions in various cancers, including esophageal cancer. The aim of this study was to investigate the effects of miR-140 on the progression of esophageal cancer and the underlying regulatory mechanism. METHODS The levels of miR-140 and zinc finger E-box-binding homeobox 2 (ZEB2) messenger RNA in esophageal cancer tissues and cell lines were measured by quantitative real-time polymerase chain reaction. The protein levels of ZEB2, β-catenin, c-Myc, and cyclinD1 were determined by Western blot. Cell proliferation and apoptosis were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and flow cytometry, respectively. Cell migration and invasion were assessed by transwell assay. In addition, the relationship between miR-140 and ZEB2 was predicted by TargetScan online database and confirmed by dual-luciferase reporter assay. The tumor xenograft model was used to verify the role of miR-140 in esophageal cancer progression in vivo. RESULTS The expression of miR-140 was downregulated whereas ZEB2 expression was upregulated in esophageal cancer tissues compared with paracancerous normal tissues. Functionally, both miR-140 overexpression and ZEB2 knockdown inhibited proliferation, migration, and invasion and induced apoptosis in esophageal cancer cells. ZEB2 overexpression reversed the effects of miR-140 on proliferation, apoptosis, migration, and invasion of esophageal cancer cells. Mechanistically, ZEB2 was identified as a target of miR-140. Furthermore, miR-140 suppressed Wnt/β-catenin pathway by regulating ZEB2 expression in esophageal cancer cells. MiR-140 inhibited tumor growth of esophageal cancer through repressing ZEB2 expression in vivo. CONCLUSIONS Our results demonstrated that miR-140 inhibited esophageal cancer development by targeting ZEB2 through inactivating Wnt/β-catenin pathway.
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Affiliation(s)
- Song Yang
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Xiangyi Li
- Department of Endocrinology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Wenhao Shen
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Haitao Hu
- Clinical Laboratory, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Chen Li
- Department of Stomatology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Gaohua Han
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, China.
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Huang C, Li J, Zhang X, Xiong T, Ye J, Yu J, Gui Y. The miR-140-5p/KLF9/KCNQ1 axis promotes the progression of renal cell carcinoma. FASEB J 2020; 34:10623-10639. [PMID: 32596959 DOI: 10.1096/fj.202000088rr] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 05/27/2020] [Accepted: 05/27/2020] [Indexed: 12/21/2022]
Abstract
Although renal cell carcinoma (RCC) is a common malignant urological cancer, its pathogenesis remains unclear. Previous studies have indicated that miR-140-5p acts as a tumor suppressor in various tumors, including bladder cancer, hepatocellular carcinoma, and gastric cancer, but its biological function in RCC remains unknown. In the present study, we found that miR-140-5p was upregulated in RCC tissues, whereas Krüppel-like factor 9 (KLF9) was downregulated and correlated inversely with miR-140-5p in RCC tissues. miR-140-5p promoted the proliferation, migration, and invasion of RCC cells in vitro, and knockdown of miR-140-5p significantly suppressed tumor growth and lung metastasis in nude mouse model of RCC. We also found that miR-140-5p significantly suppressed the expression of KLF9 by binding to the 3'-UTR of KLF9 mRNA and that KLF9, as a transcription factor, upregulates KCNQ1 (also called Kv 7.1 and Kv LQT1) expression by binding to the site (-841/-827) in the KCNQ1 promoter region in RCC cells. Moreover, forced expression of KCNQ1 decreased the growth and metastasis of RCC cells. These results suggest that the miR-140-5p/KLF9/KCNQ1 axis functions as a key signaling pathway in RCC progression and metastasis and represents a potential target of RCC therapies.
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Affiliation(s)
- Chenchen Huang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China
- Anhui Medical University, Hefei, China
| | - Jianfa Li
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China
| | - Xiaoting Zhang
- Shenzhen Bao'an District Songgang People's Hospital, Shenzhen, China
| | - Tiefu Xiong
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China
| | - Jing Ye
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China
| | - Jing Yu
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Clinical College of Anhui Medical University, Shenzhen, China
- Anhui Medical University, Hefei, China
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Hao T, Wang Z, Yang J, Zhang Y, Shang Y, Sun J. MALAT1 knockdown inhibits prostate cancer progression by regulating miR-140/BIRC6 axis. Biomed Pharmacother 2020; 123:109666. [PMID: 31935634 DOI: 10.1016/j.biopha.2019.109666] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 11/01/2019] [Accepted: 11/07/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Prostate cancer (PCa) is the second most common cancer among men globally. Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to be implicated in tumorigenesis and progression of PCa. However, the pathogenesis of MALAT1 in PCa has not been thoroughly elaborated. METHODS RT-qPCR assay was conducted to measure expression of MALAT1, microRNA-140 (miR-140) and Baculoviral IAP repeat containing 6 (BIRC6) mRNA. Protein expression of BIRC6 was detected by western blot assay. Cell proliferative ability was assessed by MTS and Edu retention assays. Cell migratory and invasive abilities were evaluated by wound healing assay and Transwell invasion assay, respectively. Cell apoptotic rate was examined using a flow cytometry. The interaction between miR-140 and MALAT1 or BIRC6 3'UTR was explored by luciferase, RNA immunoprecipitation (RIP) and RNA pull down assays. Xenograft models of PCa were established to further explore the role and molecular mechanism of MALAT in PCa tumorigenesis in vivo. RESULTS MALAT1 and BIRC6 were highly expressed in human PCa tumor tissues and cell lines. MALAT1 or BIRC6 knockdown inhibited cell proliferation, migration and invasion and induced cell apoptosis in PCa. MiR-140 could directly bind with MALAT1 or BIRC6 3'UTR. Moreover, MALAT1 knockdown inhibited BIRC mRNA and protein expression through upregulating miR-140 in PCa cells. Additionally, MALAT1 knockdown inhibited PCa xenograft tumor growth by regulating miR-140/BIRC6 axis in vivo. CONCLUSION MALAT1 knockdown hindered PCa progression by regulating miR-140/BIRC6 axis in vitro and in vivo, hinting the potential value of MALAT1 in the management of PCa.
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Affiliation(s)
- Tongtong Hao
- Department of Urology Surgery, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China
| | - Zhenghua Wang
- Department of Laboratory Medicine, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China
| | - Jinhui Yang
- Department of Urology Surgery, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China
| | - Yi Zhang
- Department of Urology Surgery, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China
| | - Yafeng Shang
- Department of Urology Surgery, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China
| | - Jiantao Sun
- Department of Urology Surgery, Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China.
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Wei F, Wang M, Li Z, Wang Y, Zhou Y. miR‑593 inhibits proliferation and invasion and promotes apoptosis in non‑small cell lung cancer cells by targeting SLUG‑associated signaling pathways. Mol Med Rep 2019; 20:5172-5182. [PMID: 31661137 PMCID: PMC6854539 DOI: 10.3892/mmr.2019.10776] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 10/07/2019] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence suggests that microRNAs (miRNAs or miRs) serve a critical role in tumor development. However, the role of miRNAs in non‑small cell lung cancer (NSCLC) progression remains largely unknown. The present study observed that miR‑593 was significantly impaired in patients with NSCLC and was a novel regulator of NSCLC progression. Patients whose tumors had high expression levels of miR‑593 had longer overall survival than patients whose tumors had low levels of miR‑593 expression (P=0.0219). miR‑593 expression levels were inversely correlated with zinc finger protein SNAI2 (SLUG) messenger RNA (mRNA) levels in 87 clinical tissue specimens of NSCLC (P<0.001). A luciferase assay demonstrated that miR‑593 interacted with the binding sites present in the SLUG 3'‑untranslated region and reduced the expression of SLUG. Introduction of a miR‑593 mimic suppressed cell proliferation by inactivating the SLUG/protein kinase B (Akt)/cyclin D1/CDK4 or CDK6 signaling pathway, while it induced apoptosis by activating the SLUG/Akt/Bcl‑2/BAX signaling pathway. Furthermore, introduction of a miR‑593 mimic recovered the expression of E‑cadherin at the protein and mRNA level, and inhibited cell migration and invasion. In conclusion, these results indicated that miR‑593 may act as a tumor suppressor in NSCLC to decelerate cancer aggressiveness by inhibiting SLUG expression.
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Affiliation(s)
- Fang Wei
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China
| | - Mofei Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China
| | - Zhen Li
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China
| | - Yong Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China
| | - Yong Zhou
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China
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12
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miR-140 targeting CTSB signaling suppresses the mesenchymal transition and enhances temozolomide cytotoxicity in glioblastoma multiforme. Pharmacol Res 2019; 147:104390. [PMID: 31398406 DOI: 10.1016/j.phrs.2019.104390] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 08/05/2019] [Accepted: 08/05/2019] [Indexed: 01/14/2023]
Abstract
Temozolomide (TMZ) is a first-line chemotherapeutic agent used against glioblastoma multiforme (GBM), but this disease exhibits recurrence and high lethality. Therefore, it is critical to explore biomarkers which involve in drug resistance and can be represented as different therapeutic effects after a diagnosis. We attempted to investigate the underlying variably expressed genes that contribute to the formation of resistance to TMZ. We analyzed gene and microRNA (miR) data from GBM patients in The Cancer Genome Atlas (TCGA) database to identify genetic factors associated with poor TMZ efficacy. By conducting a gene set enrichment analysis (GSEA), the epithelial-to-mesenchymal transition (EMT) was associated with poor TMZ responses. To identify roles of microRNAs in regulating TMZ resistance, a differential microRNA analysis was performed in TMZ-treated GBM patients. Downregulation of miR-140 was significantly correlated with poor survival. By integrating TCGA transcriptomic data and genomics of drug sensitivity in cancer (GDSC), cathepsin B (CTSB) was inversely associated with miR-140 expression and poor TMZ efficacy. By a pan-cancer analysis, both miR-140 and CTSB were found to be prognostic factors in other cancer types. We also identified that CTSB was a direct target gene of miR-140. Overexpression of miR-140 reduced CTSB levels, enhanced TMZ cytotoxicity, suppressed the mesenchymal transition, and influenced CTSB-regulated tumor sphere formation and stemness marker expression. In contrast, overexpression of CTSB decreased TMZ-induced glioma cell death, promoted the mesenchymal transition, and attenuated miR-140-increased TMZ cytotoxicity. These findings provide novel targets to increase the therapeutic efficacy of TMZ against GBM.
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13
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MicroRNA-140-5p inhibits cell proliferation, migration and promotes cell apoptosis in gastric cancer through the negative regulation of THY1-mediated Notch signaling. Biosci Rep 2019; 39:BSR20181434. [PMID: 31123165 PMCID: PMC6646234 DOI: 10.1042/bsr20181434] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 05/16/2019] [Accepted: 05/21/2019] [Indexed: 01/20/2023] Open
Abstract
Studies have highlighted the importance of microRNAs (miRs) in the development of various cancers, including gastric cancer (GC), a commonly occurring malignancy, accompanied by high recurrence and metastasis rate. The aim of the current study was to investigate the role of miR-140-5p in GC. Microarray expression profiles were initially employed to screen the differentially expressed gene related to GC, and the miR regulating the gene was predicted accordingly. The data obtained indicated that thymus cell antigen 1 (THY1) was differentially expressed in GC and confirmed to be a target gene of miR-140-5p. Poorly expressed miR-140-5p and highly expressed THY1 were observed in the GC tissues. SGC-7901 cells were treated with miR-140-5p mimic/inhibitor, siRNA against THY1 and siRNA against Notch1 in order to determine their regulatory roles in GC cell activities. The relationship of miR-140-5p, THY1 and the Notch signaling pathway was subsequently identified. Moreover, cell proliferation, migration, invasion and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), wound-healing, transwell assay and flow cytometry, respectively. The overexpression of miR-140-5p and silencing of THY1 resulted in a diminished expression of the Notch signaling pathway-related proteins, as well as inhibited proliferation, migration and invasion of GC cells, enhanced expression of pro-apoptotic proteins in addition to elevated apoptosis rate. Taken together, the present study suggests that miR-140-5p directly targets and negatively regulates THY1 expression and inhibits activation of the Notch signaling pathway, whereby the up-regulation of miR-140-5p inhibits development of GC, highlighting the promise of miR-140-5p as a potential target for GC treatment.
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14
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Zhang QY, Men CJ, Ding XW. Upregulation of microRNA-140-3p inhibits epithelial-mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN. J Cell Biochem 2019; 120:14885-14898. [PMID: 31044454 DOI: 10.1002/jcb.28750] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 02/06/2023]
Abstract
Invasion and metastasis in hepatocellular carcinoma (HCC) results in poor prognosis. Human intervention in these pathological processes may benefit the treatment of HCC. The aim of the present study is to elucidate the mechanism of miR-140-3p affecting epithelial-mesenchymal transition (EMT), invasion, and metastasis in HCC. Microarray analysis was performed for differentially expressed genes screening. The target relationship between miR-140-3p and GRN was analyzed. Small interfering RNA (siRNA) against granulin (GRN) was synthesized. EMT markers were detected, and invasion and migration were evaluated in HCC cells introduced with a miR-140-3p inhibitor or mimic, or siRNA against GRN. A mechanistic investigation was conducted for the determination of mitogen-activated protein kinase (MAPK) signaling pathway-related genes and EMT markers (E-cadherin, N-cadherin, and Vimentin). GRN was highlighted as an upregulated gene in HCC. GRN was a target gene of miR-140-3p. Elevation of miR-140-3p or inhibition of GRN restrained the EMT process and suppressed the HCC cell migration and invasion. HCC cells treated with the miR-140-3p mimic or siRNA-GRN exhibited decreased GRN expression and downregulated the expressions of the MAPK signaling pathway-related genes, N-cadherin, and Vimentin but upregulated the expression of E-cadherin. GRN silencing can reverse the activation of the MAPK signaling pathway and induction of EMT mediated by miR-140-3p inhibition. Taken together, the results show that miR-140-3p confers suppression of the MAPK signaling pathway by targeting GRN, thus inhibiting EMT, invasion, and metastasis in HCC.
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Affiliation(s)
- Qiu-Yin Zhang
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, PR China
| | - Chang-Jun Men
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, PR China
| | - Xue-Wei Ding
- Department of Gastrointestinal Tumor Surgery, Tianjin Cancer Hospital, Tianjin, PR China
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15
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Nie ZY, Liu XJ, Zhan Y, Liu MH, Zhang XY, Li ZY, Lu YQ, Luo JM, Yang L. miR-140-5p induces cell apoptosis and decreases Warburg effect in chronic myeloid leukemia by targeting SIX1. Biosci Rep 2019; 39:BSR20190150. [PMID: 30962263 PMCID: PMC6488949 DOI: 10.1042/bsr20190150] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/29/2019] [Accepted: 04/06/2019] [Indexed: 12/25/2022] Open
Abstract
microRNAs (miRNA), as tumor suppressors or oncogenes, are involved in modulating cancer cell behavior, including cell proliferation and apoptosis. The miR-140-5p acts as a tumor suppressor in several tumors, but the role of miR-140-5p in chronic myeloid leukemia (CML) remains unclear. Here, we investigated the suppression of miR-140-5p in CML patients and CML cell lines using quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Overexpression miR-140-5p in CML cells significantly inhibited cell proliferation as revealed by the CCK-8 assay and promoted cell apoptosis as revealed by flow cytometry. Moreover, the sine oculis homeobox 1 (SIX1) gene had been confirmed as a direct target of miR-140-5p using bioinformatics analysis and luciferase reporter assays. Overexpression of miR-140-5p decreased the SIX1 protein level in CML cells. SIX1 mRNA and protein levels were significantly up-regulated in CML patients and CML cell lines. Knockdown of SIX1 expression significantly inhibited CML cell proliferation and promoted cell apoptosis. Furthermore, SIX1 as a transcriptional factor positively regulated pyruvate kinase isozyme type M2 (PKM2) expression and played an important role in the Warburg effect. In addition, these findings indicated that miR-140-5p functions as a tumor suppressor and plays a critical role in CML cell apoptosis and metabolism by targeting SIX1. Moreover, the miR-140-5p/SIX1 axis may be a potential therapeutic target in CML.
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MESH Headings
- Adult
- Aged
- Apoptosis/genetics
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Leukemic
- Homeodomain Proteins/genetics
- Humans
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukocytes, Mononuclear/pathology
- Leukocytes, Mononuclear/physiology
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Middle Aged
- Thyroid Hormones/genetics
- Thyroid Hormones/metabolism
- Thyroid Hormone-Binding Proteins
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Affiliation(s)
- Zi-Yuan Nie
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Xiao-Jun Liu
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Ying Zhan
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Meng-Han Liu
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Xiao-Yan Zhang
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Zi-Ye Li
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Ya-Qiong Lu
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Jian-Min Luo
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
| | - Lin Yang
- Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China
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16
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Li Z, Li X, Du X, Zhang H, Wu Z, Ren K, Han X. The Interaction Between lncRNA SNHG1 and miR-140 in Regulating Growth and Tumorigenesis via the TLR4/NF-κB Pathway in Cholangiocarcinoma. Oncol Res 2019; 27:663-672. [PMID: 30764893 PMCID: PMC7848332 DOI: 10.3727/096504018x15420741307616] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatobiliary carcinoma. The long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been reported to contribute to the progression of multiple cancers. Nonetheless, the functions and hidden mechanism of SNHG1 remain unclear in CCA. In this study, the SNHG1 levels were boosted in CCA cell lines, and knockdown of SNHG1 repressed CCA cell proliferation and invasion in vitro. The data also demonstrated that miR-140 could act as a target of SNHG1 in CCA and inhibited CCA cell proliferation and invasion, whereas the inhibition effects were relieved by overexpression of SNHG1. In addition, Toll-like receptor 4 (TLR4), an NF-κB-activating signal, was identified to be a target of miR-140. SNHG1, as a competing endogenous RNA (ceRNA) for miR-140, enhanced TLR4 expression and activated NF-κB signaling, thereby regulating growth and tumorigenesis in CCA. Animal experiments further confirmed this conclusion. Collectively, these findings not only uncovered a key role of SNHG1/miR-140/TLR4/NF-κB signaling axis in CCA tumorigenesis and progression but also denoted the probable utilization of SNHG1 as a therapeutic target for CCA.
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Affiliation(s)
- Zhen Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xin Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xiao Du
- Beijing Genecast Biotechnology Co., Beijing, P.R. China
| | - Henghui Zhang
- Beijing Genecast Biotechnology Co., Beijing, P.R. China
| | - Zhengyang Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Kewei Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
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17
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Sun C, Zhang X, Chen Y, Jia Q, Yang J, Shu Y. MicroRNA-365 suppresses cell growth and invasion in esophageal squamous cell carcinoma by modulating phosphoserine aminotransferase 1. Cancer Manag Res 2018; 10:4581-4590. [PMID: 30410394 PMCID: PMC6197828 DOI: 10.2147/cmar.s157858] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background A number of studies have indicated that expression of miRNA-365 (miR-365) is suppressed in various cancers, suggesting its cancer-suppressive role. In the present investigation, we evaluated the regulation and character of miR-365 in human esophageal squamous cell carcinoma (ESCC). Patients and methods The tumor tissues and adjacent nontumor tissue samples were collected from 30 patients having ESCC, and the expression levels of miR-365 were studied by quantitative real-time polymerase chain reaction (PCR). MTT and cell invasion by Matrigel assay were done to study the effect of miR-365 on proliferation and metastasis of ESCC cells. An in vivo tumor model was generated by inoculating ESCC cells subcutaneously into BALB nude mice. A study of various biomarkers such as quantitative polymerase chain reaction (qPCR), luciferase activity assay, and Western blot was done to confirm the targets of miR-365. Results In tumor tissues, a significant downregulation of miR-365 was observed versus the nontumor adjacent tissues and ESCC cells versus the selected esophageal endothelial cells. It was observed that higher expression levels of miR-365 inhibited the cell invasion, colony formation, growth in esophageal cancer cell lines in vitro, and tumor development in vivo. The study of biomarkers suggests involvement of phosphoserine aminotransferase 1 (PSAT1) as a favorable target for miR-365, and its abnormal expression inverted the miR-365-arbitrated suppression of invasion, viability, and epithelial-mesenchymal transition in esophageal cancer cells. A negative correlation existed with expression of miR-365 and PSAT1 in human esophageal cancer tissue samples. Conclusion The study established that miR-365 exhibits tumor-suppressive action via regulating the levels of PSAT1 and leads to invasion and progressiveness of esophageal cancer.
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Affiliation(s)
- Changjiang Sun
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China
| | - Xizhi Zhang
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China
| | - Yong Chen
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China
| | - Qingqing Jia
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China
| | - Jianqi Yang
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China
| | - Yusheng Shu
- Department of Thoracic and Cardiovascular Surgery, Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu, China,
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18
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MiR-125a-5p suppresses bladder cancer progression through targeting FUT4. Biomed Pharmacother 2018; 108:1039-1047. [PMID: 30372804 DOI: 10.1016/j.biopha.2018.09.100] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/06/2018] [Accepted: 09/18/2018] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRNAs) have been widely studied in various human cancers, including bladder cancer. Previous report revealed that miR-125a-5p is downregulated in urothelial carcinomas. However, the biological function and molecular mechanism of miR-125a-5p in bladder cancer has not been elucidated. Therefore, this study focused on the role of miR-125a-5p in bladder cancer. The expression levels of miR-125a-5p were firstly tested in one normal cell line and four bladder cancer cell lines with qRT-PCR. The relative lower expression of miR-125a-5p was detected in bladder cancer cells. To confirm the effects of ectopic expression of miR-125a-5p on the biological behaviors of bladder cancer cells, gain-of-function assays were carried out. According to experimental results, miR-125a-5p overexpression suppressed cell proliferation and cell cycle progression, induced cell apoptosis. Moreover, overexpression of miR-125a-5p suppressed cell migration and invasion and reversed epithelial-mesenchymal transition (EMT). Mechanism investigation indicated that FUT4 is a target mRNA of miR-125a-5p in bladder cancer. The effects of FUT4 on cell proliferation, apoptosis, migration and invasion were identified by conducting gain-of-function assays. Finally, rescue assays indicated that FUT4 can reverse the effects of miR-125a-5p on bladder cancer progression. In summary, miR-125a-5p suppresses bladder cancer progression through targeting FUT4.
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19
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Moradi M, Fallahi H, Rahimi Z. Interaction of long noncoding RNA MEG3 with miRNAs: A reciprocal regulation. J Cell Biochem 2018; 120:3339-3352. [DOI: 10.1002/jcb.27604] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 08/07/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Mohammad‐Taher Moradi
- Medical Biology Research Center, Kermanshah University of Medical Sciences Kermanshah Iran
| | - Hossein Fallahi
- Medical Biology Research Center, Kermanshah University of Medical Sciences Kermanshah Iran
- Bioinformatics Lab, Department of Biology School of Sciences, Razi University Kermanshah Iran
| | - Zohreh Rahimi
- Medical Biology Research Center, Kermanshah University of Medical Sciences Kermanshah Iran
- Department of Clinical Biochemistry Medical School, Kermanshah University of Medical Sciences Kermanshah Iran
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20
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Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition. Noncoding RNA 2018; 4:ncrna4020014. [PMID: 29843425 PMCID: PMC6027143 DOI: 10.3390/ncrna4020014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 01/17/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell⁻cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.
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21
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In silico identification of microRNAs predicted to regulate N-myristoyltransferase and Methionine Aminopeptidase 2 functions in cancer and infectious diseases. PLoS One 2018; 13:e0194612. [PMID: 29579063 PMCID: PMC5868815 DOI: 10.1371/journal.pone.0194612] [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: 12/25/2017] [Accepted: 03/06/2018] [Indexed: 01/16/2023] Open
Abstract
Protein myristoylation is a key protein modification carried out by N-Myristoyltransferase (NMT) after Methionine aminopeptidase 2 (MetAP2) removes methionine from the amino-terminus of the target protein. Protein myristoylation by NMT augments several signaling pathways involved in a myriad of cellular processes, including developmental pathways and pathways that when dysregulated lead to cancer or immune dysfunction. The emerging evidence pointing to NMT-mediated myristoylation as a major cellular regulator underscores the importance of understanding the framework of this type of signaling event. Various studies have investigated the role that myristoylation plays in signaling dysfunction by examining differential gene or protein expression between normal and diseased states, such as cancers or following HIV-1 infection, however no study exists that addresses the role of microRNAs (miRNAs) in the regulation of myristoylation. By performing a large scale bioinformatics and functional analysis of the miRNAs that target key genes involved in myristoylation (NMT1, NMT2, MetAP2), we have narrowed down a list of promising candidates for further analysis. Our condensed panel of miRNAs identifies 35 miRNAs linked to cancer, 21 miRNAs linked to developmental and immune signaling pathways, and 14 miRNAs linked to infectious disease (primarily HIV). The miRNAs panel that was analyzed revealed several NMT-targeting mRNAs (messenger RNA) that are implicated in diseases associated with NMT signaling alteration, providing a link between the realms of miRNA and myristoylation signaling. These findings verify miRNA as an additional facet of myristoylation signaling that must be considered to gain a full perspective. This study provides the groundwork for future studies concerning NMT-transcript-binding miRNAs, and will potentially lead to the development of new diagnostic/prognostic biomarkers and therapeutic targets for several important diseases.
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22
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Li J, Zou K, Yu L, Zhao W, Lu Y, Mao J, Wang B, Wang L, Fan S, Song B, Li L. MicroRNA-140 Inhibits the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 10:426-437. [PMID: 29499953 PMCID: PMC5862396 DOI: 10.1016/j.omtn.2017.12.022] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/30/2017] [Accepted: 12/30/2017] [Indexed: 12/21/2022]
Abstract
MicroRNA-140, a cartilage-specific microRNA, has recently been implicated in the cancer progression. However, the comprehensive role of miR-140 in the invasion and metastasis of colorectal cancer (CRC) is still not fully understood. In this study, we confirmed that miR-140 downregulates SMAD family member 3 (Smad3), which is a key downstream effector of the TGF-β signaling pathway, at the translational level in the CRC cell lines. Ectopic expression of miR-140 inhibits the process of epithelial-mesenchymal transition (EMT), at least partially through targeting Smad3, and induces the suppression of migratory and invasive capacities of CRC cells in vitro. miR-140 also attenuates CRC cell proliferation possibly via downregulating Samd3. Furthermore, overexpression of miR-140 inhibits the tumor formation and metastasis of CRC in vivo, and silenced Smad3 has the similar effect. Additionally, miR-140 expression is decreased in the clinical primary CRC specimens and appears as a progressive reduction in the metastatic specimens, whereas Smad3 is overexpressed in the CRC samples. Taken together, our findings suggest that miR-140 might be a key suppressor of CRC progression and metastasis through inhibiting EMT process by targeting Smad3. miR-140 may represent a novel candidate for CRC treatment.
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Affiliation(s)
- Jiazhi Li
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Kun Zou
- Department of Oncology Radiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Lihui Yu
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Wenyue Zhao
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Ying Lu
- Department of Pathology, Dalian Medical University, Dalian 116044, China; Teaching Laboratory of Morphology, Dalian Medical University, Dalian 116044, China
| | - Jun Mao
- Department of Pathology, Dalian Medical University, Dalian 116044, China; The Key Laboratory of Tumor Stem Cell Research of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Bo Wang
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Lu Wang
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Shujun Fan
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Bo Song
- Department of Pathology, Dalian Medical University, Dalian 116044, China; Teaching Laboratory of Morphology, Dalian Medical University, Dalian 116044, China.
| | - Lianhong Li
- Department of Pathology, Dalian Medical University, Dalian 116044, China; The Key Laboratory of Tumor Stem Cell Research of Liaoning Province, Dalian Medical University, Dalian 116044, China.
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Fang Z, Yin S, Sun R, Zhang S, Fu M, Wu Y, Zhang T, Khaliq J, Li Y. miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1. Mol Cancer 2017; 16:139. [PMID: 28818100 PMCID: PMC5561618 DOI: 10.1186/s12943-017-0708-6] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 08/07/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The aberrant expression of microRNA-140-5p (miR-140-5p) has been described in gastric cancer (GC). However, the role of miR-140-5p in GC remains unclear. In this study, the prognostic relevance of miR-140-5p in GC was investigated and YES1 was identified as a novel target of miR-140-5p in regulating tumor progression. METHODS miR-140-5p level was determined in 20 paired frozen specimens through quantitative real-time PCR, and analyzed in tissue microarrays through in situ hybridization. The target of miR-140-5p was verified through a dual luciferase reporter assay, and the effects of miR-140-5p on phenotypic changes in GC cells were investigated in vitro and in vivo. RESULTS Compared with that in adjacent normal tissues, miR-140-5p expression decreased in cancerous tissues. The downregulated miR-140-5p in 144 patients with GC was significantly correlated with the reduced overall survival of these patients. miR-140-5p could inhibit GC cell proliferation, migration and invasion by directly targeting 3'-untranlated region of YES1. miR-140-5p could also remarkably reduce the tumor size in GC xenograft mice. CONCLUSIONS miR-140-5p serves as a potential prognostic factor in patients with GC, and miR-140-5p mediated YES1 inhibition is a novel mechanism behind the suppressive effects of miR-140-5p in GC.
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Affiliation(s)
- Zheng Fang
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Shuai Yin
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of University of Munich, Marchioninistr.15, 5H-02-428, 81377, Munich, Germany
| | - Ruochuan Sun
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Shangxin Zhang
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Min Fu
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Youliang Wu
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Tao Zhang
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Junaid Khaliq
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China
| | - Yongxiang Li
- Department of General Surgery, First affiliated Hospital of Anhui Medical University, 218 Jixi Avenue, Hefei, 230022, China.
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24
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MicroRNA-140-5p inhibits invasion and angiogenesis through targeting VEGF-A in breast cancer. Cancer Gene Ther 2017; 24:386-392. [PMID: 28752859 PMCID: PMC5668497 DOI: 10.1038/cgt.2017.30] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 06/16/2017] [Accepted: 06/19/2017] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) have been proven to be involved in cell metastasis and angiogenesis by interaction with the target mRNAs. Evidence has been confirmed that miR-140-5p is a tumor suppressor in human cancers such as breast cancer. However, the potential molecular mechanism of miR-140-5p in breast cancer invasion and angiogenesis is still poorly understood. According to our study, we reported that miR-140-5p inhibited the tumor invasion and angiogenesis of breast cancer cells both in vitro and in vivo by targeting VEGF-A. The mRNA amount of miR-140-5p was decreased in the breast cancer clinical samples and breast cancer with metastasis compared with the corresponding adjacent normal tissues and cancer without metastasis. MiR-140-5p mimics and a negative control were transfected into human MCF-7 and MDA-MB-231 cells. Transwell chambers were used to detect the invasive ability of the cells, and the angiogenic ability was assessed by tube-formation assay. The markers of invasion and angiogenesis, VEGF-A, CD31 and MMP-9, were detected by using immunohistochemistry and western blot analysis in vivo. VEGF-A was verified as a possible target gene of miR-140-5p, and corroborated by dual-luciferase reporter and ELISA. Taken together, the study elucidates the molecular mechanisms by which miR-140-5p inhibits breast cancer metastasis and angiogenesis, and provides a potent evidence for the development of a novel microRNA-targeting anticancer strategy for breast cancer patients.
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25
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Ma Z, Feng J, Guo Y, Kong R, Ma Y, Sun L, Yang X, Zhou B, Li S, Zhang W, Jiang J, Zhang J, Qiao Z, Cheng Y, Zha D, Liu S. Knockdown of DDX5 Inhibits the Proliferation and Tumorigenesis in Esophageal Cancer. Oncol Res 2017; 25:887-895. [PMID: 28244855 PMCID: PMC7841059 DOI: 10.3727/096504016x14817158982636] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
DEAD (Asp-Glu-Ala-Asp) box protein 5 (DDX5), a prototypical member of the DEAD/H-box protein family, has been involved in several human malignancies. However, the expression and biological role of DDX5 in esophageal cancer (EC) remain largely unknown. In this study, we examined the role of DDX5 in regulating EC cell proliferation and tumorigenesis and explored its possible molecular mechanism. We found that DDX5 was overexpressed in human EC cell lines. In addition, knockdown of DDX5 significantly inhibited the proliferation of EC cells in vitro and the growth of EC xenografts in vivo. Knockdown of DDX5 also suppressed the migration/invasion and epithelial-to-mesenchymal transition (EMT) phenotype in EC cells. Furthermore, we observed that knockdown of DDX5 inhibited the expression of β-catenin, c-Myc, and cyclin D1 in EC cells. In conclusion, our findings provide the first evidence that siRNA-DDX5 inhibited the proliferation and invasion of EC cells through suppressing the Wnt/β-catenin signaling pathway. Therefore, DDX5 may be a novel potential therapeutic target for the prevention and treatment of EC.
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Affiliation(s)
- Zhenchuan Ma
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Jie Feng
- †Department of Nephrology, The First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Yurui Guo
- ‡Department of Anesthesia, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Ranran Kong
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Yuefeng Ma
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Liangzhang Sun
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Xiaoping Yang
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Bin Zhou
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Shaomin Li
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Wei Zhang
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Jiantao Jiang
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Jin Zhang
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Zhe Qiao
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Yao Cheng
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Danjie Zha
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
| | - Shiyuan Liu
- *Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
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26
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MiR-140/BDNF axis regulates normal human astrocyte proliferation and LPS-induced IL-6 and TNF-α secretion. Biomed Pharmacother 2017; 91:899-905. [DOI: 10.1016/j.biopha.2017.05.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/03/2017] [Accepted: 05/04/2017] [Indexed: 01/12/2023] Open
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27
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Wang G, Zhao W, Gao X, Zhang D, Li Y, Zhang Y, Li W. HNF1A‑AS1 promotes growth and metastasis of esophageal squamous cell carcinoma by sponging miR‑214 to upregulate the expression of SOX-4. Int J Oncol 2017; 51:657-667. [PMID: 28656277 DOI: 10.3892/ijo.2017.4034] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/22/2017] [Indexed: 11/05/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world, marked by dysphagia and weight loss, bringing great suffering to patients. HNF1A‑AS1 (HAS1), a long non-coding RNA (lncRNA), has been identified prevalently involved in various human cancers. However, the exact effects and molecular mechanisms of HAS1 in ESCC progression are still elusive. In this study, upregulated expression of HAS1 was detected in ESCC tissues and four human ESCC cell lines (KYSE70, KYSE450, EC109 and EC970) compared with normal tissues and cell lines. Small interfering RNA (siRNA)-mediated knockdown of HAS1 largely suppressed cell proliferation and promoted cell apoptosis in KYSE70 and EC109 cells. The decreased expression of proliferation marker proteins and elevated level of apoptosis marker proteins further verified that HAS1‑siRNA suppressed cell viability in ESCC cells. Besides, the silence of HAS1 strongly reduced the wound closing rate and the number of invasive cells compared with control group. HAS1-siRNA also restrained the expression of migration marker proteins matrix metalloproteinase-9 (MMP-9) and vascular endothelial cell growth factor (VEGF). In addition, miR‑214 was predicted as a direct target of HAS1 by bioinformatics analysis. Downregulated expression of miR‑214 was elevated in KYSE70 and EC109 cells transfected with HAS1-siRNA. Subsequently, elevated expression of miR‑214 was suppressed by co-transfecting with miR‑214 inhibitor in EC109 cells pretreated with HAS1-siRNA. The result of luciferase activity assay showed that luciferase activity was strongly weakened by the combination of LncR-HAS1 WT and miR‑214 mimic. Moreover, the expression of SOX-4, a predicted target gene of miR‑214, was suppressed by HAS1-siRNA and was increased by miR‑214 inhibitor. HAS1-siRNA counteracted the effect of miR‑214 inhibitor on cell viability and mobility in EC109 cells. Finally, the in vivo experiment revealed that HAS1-siRNA abated the role of miR‑214 inhibitor in promoting tumor growth and metastasis. miR-214 also mediated the effect of HAS1 on upregulating the expression of SOX-4 in vivo. Taken together, our study indicated a HAS1-miR‑214-SOX-4 pathway in regulating the growth and metastasis of ESCC, providing a promising target for ESCC therapy.
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Affiliation(s)
- Guannan Wang
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Wugan Zhao
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xianzheng Gao
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Dandan Zhang
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ye Li
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yanping Zhang
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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28
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Xiao JN, Yan TH, Yu RM, Gao Y, Zeng WL, Lu SW, Que HX, Liu ZP, Jiang JH. Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression. J Cancer Res Clin Oncol 2017; 143:981-990. [PMID: 28271214 DOI: 10.1007/s00432-017-2370-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 02/12/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Long non-coding RNA (LncRNA) urothelial carcinoma-associated 1 (UCA1) is reported to be dysregulated in hepatocellular carcinoma (HCC) progression. However, the functions of UCA1 in HCC still need further study. The aim is to detect the role of UCA1 involving in HCC cells proliferation and invasion, and epithelial-mesenchymal transition (EMT). METHODS The quantitative real-time PCR was used to detect the UCA1 and miR-203 expression levels in 60 cases' HCC tissues and adjacent normal tissues. Western blotting analysis was performed to detect the EMT markers E-cadherin, Vimentin and transcription factor Snail1, Snail2 expression. Luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays were used to evaluate whether miR-203 was a target of UCA1. RESULTS Our results showed that UCA1 was markedly upregulated in HCC tissues and higher UCA1 expression in HCC was positively associated with tumor size, vascular invasion and American Joint Committee on Cancer (AJCC) stage (P < 0.05). Furthermore, gain-of-function and loss-of-function analysis showed that UCA1 knockdown inhibited HCC cells proliferation and invasion in vitro and xenograft tumour growth in vivo. Moreover, UCA1 overexpression promoted cell epithelial-mesenchymal transition (EMT) in HCC via effectively sponging to miR-203 and thereby activating the expression of transcription factor Snail2. CONCLUSIONS Our results identified that UCA1/miR-203/Snail2 pathway might involve in HCC progression. Inhibition of UCA1 acted as a promising therapeutic target for HCC patients.
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Affiliation(s)
- Ji-Nan Xiao
- Department of Radiotherapy, Second Hospital of Longyan City, Longyan, 364000, Fujian, China
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Ting-Hua Yan
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Rui-Ming Yu
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Yi Gao
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Wen-Long Zeng
- Department of Radiotherapy, Second Hospital of Longyan City, Longyan, 364000, Fujian, China
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Sui-Wan Lu
- Department of Radiotherapy, Second Hospital of Longyan City, Longyan, 364000, Fujian, China
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Hua-Xing Que
- Department of Radiotherapy, Second Hospital of Longyan City, Longyan, 364000, Fujian, China
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Ze-Ping Liu
- Department of Radiotherapy, Second Hospital of Longyan City, Longyan, 364000, Fujian, China
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China
| | - Jin-Hua Jiang
- Department of Oncology and Internal Medicine, Humanity Hospital of Longyan City, Longyan, 364000, Fujian, China.
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29
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Zhang Q, Luo Q, Yuan X, Chai L, Li D, Liu J, Lv Z. Atmospheric particulate matter 2.5 promotes the migration and invasion of hepatocellular carcinoma cells. Oncol Lett 2017; 13:3445-3450. [PMID: 28521450 PMCID: PMC5431175 DOI: 10.3892/ol.2017.5947] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 02/20/2017] [Indexed: 01/10/2023] Open
Abstract
Epidemiological data has demonstrated that particulate matter (PM) with an aerodynamic diameter ≤ 2.5 µm (PM2.5) is associated with cancer incidence. However, the precise mechanisms underlying PM2.5-mediated hepatocellular carcinoma cancer (HCC) migration and invasion remain unclear. The aim of the present study was to explore the response of the HCC cell lines HepG2 and HuH-7 to PM2.5 exposure. The results revealed that PM2.5 treatment promoted the migration and invasion of HCC cells, in addition to increasing protein levels of matrix metalloproteinase (MMP)-13. Additionally, PM2.5 induced intracellular reactive oxygen species formation in HCC cells. Further investigation revealed that phosphorylation of RAC-alpha serine/threonine-protein kinase (AKT) increased in response to PM2.5 exposure in HCC cells, and the AKT antagonist LY294002 reduced PM2.5-induced migration, invasion and MMP-13 expression. In addition, the data from the present study demonstrated that high concentrations of PM2.5 decreased the proliferation of normal HL7702 hepatocyte cells and promoted apoptosis. These results indicate that the activation of AKT by PM2.5 results in MMP-13 overexpression, and stimulates HCC cell migration and invasion. In conclusion, the results from the present study demonstrate that PM2.5 promotes HCC development and elucidate a potential underlying molecular mechanism for this effect.
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Affiliation(s)
- Qian Zhang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Qiong Luo
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xueyu Yuan
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Li Chai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Dan Li
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Jianjun Liu
- Department of Intensive Care Unit, Central Hospital of Zhabei District, Shanghai 200000, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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30
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MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy. Sci Rep 2017; 7:416. [PMID: 28341864 PMCID: PMC5428500 DOI: 10.1038/s41598-017-00405-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022] Open
Abstract
Chemotherapy is an important treatment modality for osteosarcoma. However, it often fails because of chemoresistance, especially multidrug resistance. Previously, we found several genes were involved in chemoresistance development. In this report, we used high-throughput microRNA (miRNA) expression analysis to reveal that expression of miR-140-5p was associated with chemosensitivity in osteosarcoma. The exact roles of miR-140-5p in the chemoresistance of osteosarcoma were then investigated, we found that knockdown of miR-140-5p enhanced osteosarcoma cells resistance to multiple chemotherapeutics while overexpression of miR-140-5p sensitized tumors to chemotherapy in vitro. Moreover, in vivo, knockdown of miR-140-5p also increased the osteosarcoma cells resistance to chemotherapy. Luciferase assay and Western blot analysis showed that HMGN5 was the direct target of miR-140-5p which could positively regulated autophagy. Silencing these target genes by siRNA or inhibition of autophagy sensitized osteosarcoma cells to chemotherapy. These findings suggest that a miR-140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma. In conclusion, our data elucidated that miR-140-5p promoted autophagy mediated by HMGN5 and sensitized osteosarcoma cells to chemotherapy. These results suggest a potential application of miR-140-5p in overall survival, chemoresistance prognosis and treatment.
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31
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Xiao Q, Huang L, Zhang Z, Chen X, Luo J, Zhang Z, Chen S, Shu Y, Han Z, Cao K. Overexpression of miR-140 Inhibits Proliferation of Osteosarcoma Cells via Suppression of Histone Deacetylase 4. Oncol Res 2017; 25:267-275. [PMID: 27624383 PMCID: PMC7840736 DOI: 10.3727/096504016x14732510786564] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
miRNAs play a pivotal role in the development and progression of osteosarcoma (OS). Previous studies indicated that miR-140 acts as a tumor suppressor in many cancers. However, its accurate expression and exact function in OS cells remain unknown. Herein, we demonstrated the lower expression of miR-140 in 40 paired OS tissues. Restoring miR-140 expression in OS cells had a marked effect on inhibiting cell proliferation and invasion, inducing cell apoptosis in vitro, and suppressing tumor growth in vivo. Moreover, a bioinformatics prediction indicated that the histone deacetylase 4 (HDAC4) is a target gene of miR-140 and is involved in miR-140-mediated suppressive effects. In conclusion, our findings show that miR-140 acts as a tumor suppressor in OS by targeting HDAC4.
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Affiliation(s)
- Qianren Xiao
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Lu Huang
- †Department of Children Health and Care, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, P.R. China
| | - Zhongzu Zhang
- ‡Department of Orthopedics, The Yongchuan Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Xiang Chen
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Jiaquan Luo
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Zhanmin Zhang
- §Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Shaoqing Chen
- §Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Yong Shu
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Zhimin Han
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Kai Cao
- *Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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32
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Yu L, Lu Y, Han X, Zhao W, Li J, Mao J, Wang B, Shen J, Fan S, Wang L, Wang M, Li L, Tang J, Song B. microRNA -140-5p inhibits colorectal cancer invasion and metastasis by targeting ADAMTS5 and IGFBP5. Stem Cell Res Ther 2016; 7:180. [PMID: 27906093 PMCID: PMC5134063 DOI: 10.1186/s13287-016-0438-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/13/2016] [Accepted: 11/10/2016] [Indexed: 02/08/2023] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignancies in the world. microRNA-140-5p (miR-140) has been shown to be involved in cartilage development and osteoarthritis (OA) pathogenesis. Some contradictions still exist concerning the role of miR-140 in tumor progression and metastasis, and the underlying mechanism is uncertain. Methods Immunohistochemistry was performed to determine the expressions of ADAMTS5 and IGFBP5 in CRC tissues. Human CRC cell lines HCT116 and RKO were transfected with miR-140 mimic, inhibitor, or small interfering RNA (siRNA) against ADAMTS5 or IGFBP5, respectively, using oligofectamine or lipofectamine 2000. Scratch-wound assay and transwell migration and invasion assays were used to evaluate the effects of miR-140 on the capabilities of migration and invasion. The levels of miR-140 and ADAMTS5 and IGFBP5 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of ADAMTS5 and IGFBP5 proteins. Results miR-140 was significantly reduced, whereas ADAMTS5 and IGFBP5 were upregulated, in the human CRC tissues compared to the corresponding normal colorectal mucosa. miR-140 downregulation and ADAMTS5 or IGFBP5 overexpression were associated with the advanced TNM stage and distant metastasis of CRC. There was a reverse correlation between miR-140 levels and ADAMTS5 and IGFBP5 expression in CRC tissues. ADAMTS5 and IGFBP5 were downregulated by miR-140 at both the protein and mRNA levels in the CRC cell lines. The gain-of- and loss-of-function studies showed that miR-140 inhibited CRC cell migratory and invasive capacities at least partially via downregulating the expression of ADAMTS5 and IGFBP5. Conclusions These findings suggest that miR-140 suppresses CRC progression and metastasis, possibly through downregulating ADAMTS5 and IGFBP5. miR-140 might be a potential therapeutic candidate for the treatment of CRC.
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Affiliation(s)
- Lihui Yu
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Ying Lu
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China.,Teaching Laboratory of Morphology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China
| | - Xiaocui Han
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Wenyue Zhao
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Jiazhi Li
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Jun Mao
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China.,Key Laboratory of Tumor Stem Cell Research of Liaoning Province, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Bo Wang
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Jie Shen
- Teaching Laboratory of Morphology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China
| | - Shujun Fan
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Lu Wang
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Mei Wang
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China.,Key Laboratory of Tumor Metastasis Research of Liaoning Province, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Lianhong Li
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China.,Key Laboratory of Tumor Stem Cell Research of Liaoning Province, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Jianwu Tang
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China.,Key Laboratory of Tumor Metastasis Research of Liaoning Province, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Bo Song
- Department of Pathology, Dalian Medical University, Dalian, 116044, People's Republic of China. .,Teaching Laboratory of Morphology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China.
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Liu HT, Gao P. The roles of microRNAs related with progression and metastasis in human cancers. Tumour Biol 2016; 37:15383–15397. [PMID: 27714675 DOI: 10.1007/s13277-016-5436-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 09/23/2016] [Indexed: 02/06/2023] Open
Abstract
Metastasis is an important factor in predicting the prognosis of the patients with cancers and contributes to high cancer-related mortality. Recent studies indicated that microRNAs (miRNAs) played a functional role in the initiation and progression of human malignancies. MicroRNAs are small non-coding RNAs of about 22 nucleotides in length that can induce messenger RNA (mRNA) degradation or repress mRNA translation by binding to the 3' untranslated region (3'-UTR) of their target genes. Overwhelming reports indicated that miRNAs could regulate cancer invasion and metastasis via epithelial-to-mesenchymal transition (EMT)-related and/or non-EMT-related mechanisms. In this review, we concentrate on the underlying mechanisms of miRNAs in regulating cancer progression and metastasis.
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Affiliation(s)
- Hai-Ting Liu
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, People's Republic of China
- Department of Pathology, School of Basic Medicine, Shandong University, Jinan, People's Republic of China
| | - Peng Gao
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
- Department of Pathology, School of Basic Medicine, Shandong University, Jinan, People's Republic of China.
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34
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Peng Z, Xu T, Liao X, He H, Xu W. Effects of radiotherapy on nasopharyngeal carcinoma cell invasiveness. Tumour Biol 2016; 37:15559–15566. [PMID: 26318302 DOI: 10.1007/s13277-015-3960-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 08/19/2015] [Indexed: 12/25/2022] Open
Abstract
Radiotherapy is widely used in the treatment of nasopharyngeal carcinoma (NPC), whereas its effects on the NPC growth, survival, and metastases have not been completely evaluated. Here, we compared the detected metastatic NPC tissues after radiotherapy (m-NPC) to the resected primary NPC tissues prior to radiotherapy (p-NPC). We detected higher levels of Snail2 protein, but not mRNA in m-NPC, compared to p-NPC. In vitro, a modest irradiation on NPC cells resulted in significant cell death, but increased Snail2 protein, but mRNA levels in the surviving NPC cells. Bioinformatics analyses showed that miR-613, which was significantly decreased in NPC cells after irradiation, targeted the 3'-UTR of Snail2 mRNA to inhibit its translation. Moreover, miR-613 overexpression inhibited Snail2-mediated cell invasiveness, while miR-613 depletion increased Snail2-mediated cell invasiveness in NPC cells. Finally, we detected significantly lower levels of miR-613 in m-NPC, compared to p-NPC. Together our data suggest that although radiotherapy induced NPC cell death, it may increase Snail2-mediated NPC cell invasiveness through downregulating miR-613.
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Affiliation(s)
- Zheng Peng
- Department of Radiation Oncology, Quzhou People Hospital, Zhongloudi Road, Quzhou, 324000, China,
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Liu X, Wang S, Yuan A, Yuan X, Liu B. MicroRNA-140 represses glioma growth and metastasis by directly targeting ADAM9. Oncol Rep 2016; 36:2329-38. [PMID: 27498787 DOI: 10.3892/or.2016.5007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 07/18/2016] [Indexed: 11/05/2022] Open
Abstract
Glioma is the most frequent primary malignant tumor of the human brain. Recently, great progress has been made in the combined therapy of glioma. However, the clinical effects of these treatments and prognosis for patients with glioma remains poor. MicroRNAs (miRNAs) have been demonstrated to play important roles in the initiation and progression of various types of human cancers, also including glioma. The present study investigated the expression patterns of microRNA‑140 (miR-140) in glioma, and the roles of miR-140 in glioma cell proliferation, migration and invasion. The results showed that miR-140 was significantly downreuglated in glioma tissues and cell lines, and low expression levels of miR-140 were correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) of glioma patients. Restoration of miR-140 obviously suppressed glioma cell proliferation, migration and invasion. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified as a novel direct target gene of miR-140 in glioma. Furthermore, knockdown of ADAM9 simulated the tumor suppressor functions of miR-140, while overexpression of ADAM9 abrogated these suppressive effects induced by miR-140 in glioma cells. In conclusion, the present study demonstrated the expression and clinical roles of miR-140 in glioma and suggested that miR-140 inhibited proliferation, migration and invasion of glioma cells, partially at least via suppressing ADAM9 expression. Therefore, miR-140 may be a novel candidate target for the development of therapeutic strategies for patients with glioma.
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Affiliation(s)
- Xiaogang Liu
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Shanjun Wang
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Aiqin Yuan
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Xunhui Yuan
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Bing Liu
- Department of Neurosurgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261030, P.R. China
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Long non-coding RNA Unigene56159 promotes epithelial-mesenchymal transition by acting as a ceRNA of miR-140-5p in hepatocellular carcinoma cells. Cancer Lett 2016; 382:166-175. [PMID: 27597739 DOI: 10.1016/j.canlet.2016.08.029] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 08/30/2016] [Accepted: 08/31/2016] [Indexed: 12/19/2022]
Abstract
HBV infection has been reported to be closely associated with HCC development; however, the underlying mechanisms are unclear. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) play important regulatory roles in the pathogenesis and progression of cancers. To investigate the important role and mechanism of lncRNAs in the progression of HBV-related HCC, we screened lncRNAs in HBV-positive and HBV-negative HCC tissues. We identified a novel lncRNA, lncRNA-Unigene56159, which is highly expressed in HBV-related HCC tissues, and further analysis showed that this lncRNA was induced by HBV in vitro. Functionally, Unigene56159 significantly promoted cell migration/invasion and epithelial-mesenchymal transition (EMT) in HCC. Mechanistically, Unigene56159 could directly bind to miR-140-5p and effectively act as a competing endogenous RNA (ceRNA) for miR-140-5p to de-repress the expression of the target gene Slug. Collectively, our findings indicate that the Unigene56159/miR-140-5p/Slug axis contributes to HCC cell migration and invasion, which may provide novel insights into the function of lncRNA-driven hepatocarcinogenesis.
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Zou J, Xu Y. MicroRNA-140 Inhibits Cell Proliferation in Gastric Cancer Cell Line HGC-27 by Suppressing SOX4. Med Sci Monit 2016; 22:2243-52. [PMID: 27353653 PMCID: PMC4930272 DOI: 10.12659/msm.896633] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 12/17/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastric cancer is a malignant tumor with a high morbidity and mortality. MicroRNAs are important regulators of gene expression, influencing the progression of gastric cancer. This study aimed to reveal the role of microRNA-140 (miR-140) in gastric cancer cell proliferation and its potential mechanisms. MATERIAL AND METHODS Gastric cancer tissues and cell lines BGC-823, SGC-7901, and HGC-27 were used to analyze miR-140 levels compared to normal tissues and cell line GES-1. In HGC-27 cells transfected with miR-140 mimic, we performed MTT, colony formation assay, and cell cycle assay by flow cytometry. SOX4, a predicted target of miR-140, was mutated to verify its regulation by miR-140, and was overexpressed to analyze its function in cell proliferation. Doxorubicin treatment was performed to investigate the effect of miR-140 on drug resistance. RESULTS miR-140 was down-regulated in gastric cancer tissues and cell lines, with the lowest expression level in HGC-27. miR-140 overexpression inhibited HGC-27 cell viability and colony formation and resulted in G0/G1 arrest. miR-140 suppressed SOX4 expression via binding to the 3' untranslated region, while the mutant SOX4 could not be regulated. Overexpressing SOX4 led to promoted cell viability, colony formation, and cell cycle progress. miR-140 overexpression also improved the anti-viability effects of doxorubicin, suggesting its potential in reducing the drug resistance of gastric cells. CONCLUSIONS These findings suggest that miR-140 directly inhibits SOX4, which might be one of its mechanisms in suppressing gastric cancer cell proliferation. This study provides a promising therapeutic strategy for treating gastric cancer and facilitates microRNA research in various diseases.
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Affiliation(s)
| | - Youqing Xu
- Corresponding Author: Youqing Xu, e-mail:
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Abstract
MicroRNAs (miRNA) are 22-nucleotide non-coding RNAs that post-transcriptionally regulate gene expression by base pairing to partially complementary sequences in the 3'-untranslated region of their target messenger RNA. Altered miRNA expression also changes the expression of oncogenes and tumor suppressors, affecting the proliferation, apoptosis, motility and invasibility of gastrointestinal cancer cells, including the cells of esophageal squamous cell carcinoma (ESCC). It has been suggested that various miRNA expression profiles may provide useful biomarkers and therapeutic targets, but to date few studies have been published on the role of miRNA in ESCC. In this review we summarize the identification and characterization of miRNAs involved in ESCC and discuss their potential as biomarkers and therapeutic targets.
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Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget 2016; 6:19735-46. [PMID: 25980495 PMCID: PMC4637317 DOI: 10.18632/oncotarget.3771] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/15/2015] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-β signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreased cell invasion and proliferation, and increasing cell cycle arrest. Ectopic expression of hsa-miR-140-5p in colorectal CSCs inhibited CSC growth and sphere formation in vitro by disrupting autophagy. We have systematically identified targets of hsa-miR-140-5p involved in autophagy. Furthermore, overexpression of hsa-miR-140-5p in CSCs abolished tumor formation and metastasis in vivo. In addition, there is a progressive loss of hsa-miR-140-5p expression from normal colorectal mucosa to primary tumor tissues, with further reduction in liver metastatic tissues. Higher hsa-miR-140 expression is significantly correlated with better survival in stage III and IV colorectal cancer patients. The functional and clinical significance of hsa-miR-140-5p suggests that it is a key regulator in CRC progression and metastasis, and may have potential as a novel therapeutic molecule to treat CRC.
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40
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Wu Z, Li X, Cai X, Huang C, Zheng M. miR-497 inhibits epithelial mesenchymal transition in breast carcinoma by targeting Slug. Tumour Biol 2015; 37:7939-50. [PMID: 26700673 DOI: 10.1007/s13277-015-4665-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 12/16/2015] [Indexed: 12/21/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) is a critical step in the growth and dissemination of malignant diseases, including breast cancer. It is known that microRNAs (miRNAs) play important roles in the regulation of tumor properties in cancers. However, whether miR-497 contributes to EMT in breast cancer cells remains unknown. Our study demonstrated that the expression of miR-497 was significantly decreased in human breast cancer cell lines and breast cancer specimens. In breast cancer cells, EMT was inhibited and promoted by the over-expression as well as depletion of miR-497, respectively. Dual-Luciferase ReporterAassay confirmed that Slug was a direct target of miR-497. The upregulation of miR-497 in breast cancer cells suppressed cell proliferation and induced apoptosis both in vitro and in vivo. Correlation analysis indicated that miR-497 was highly negatively correlated with Slug expression in breast cancer specimens. The knockdown of Slug expression in breast cancer cells significantly suppressed cell proliferation and promoted apoptosis. Our results suggested that the expression of miR-497 is significantly correlated with EMT in breast cancer cells by regulating Slug at the transcriptional as well as translational levels. Therefore, targeting miR-497 may provide a novel strategy for the treatment of breast cancer.
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Affiliation(s)
- Zhihao Wu
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China
| | - Xiangli Li
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China
| | - Xuehong Cai
- Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China
| | - Chenggang Huang
- Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China
| | - Min Zheng
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China. .,Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China.
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Luo H, Guo W, Wang F, You Y, Wang J, Chen X, Wang J, Wang Y, Du Y, Chen X, Xue C, Song G, Wang F. miR-1291 targets mucin 1 inhibiting cell proliferation and invasion to promote cell apoptosis in esophageal squamous cell carcinoma. Oncol Rep 2015; 34:2665-73. [PMID: 26324125 DOI: 10.3892/or.2015.4206] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 07/10/2015] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs) are well known as important regulators in various cancer development. In the present study, we focused on the expression and biological function of miR-1291 in esophageal squamous cell carcinoma (ESCC). Compared with adjacent non-tumorous tissue samples, qRT-PCR data showed significant downregulation of miR-1291 in 54 ESCC tissue samples (P<0.05), which was also significantly associated with lymph node metastases and clinical stage (P<0.05). Cell Counting Kit-8 (CCK-8), colony formation, Transwell and flow cytometric apoptosis assays were performed to detect the effect of miR-1291 upregulation, and the results showed inhibition of the proliferation, invasion and promotion of apoptosis in EC9706 and EC-1 cells. Using bioinformatic analyses, we found that mucin 1 (MUC1) was a potential target for miR-1291. Luciferase assays were performed to reveal that miR-1291 inhibited MUC1 expression by targeting the seed region of MUC1 3'-untranslated region (3'UTR). We also found that the expression of MUC1 lacking in 3'UTR abrogated the anti-invasion and pro-apoptosis function of miR-1291. Our results demonstrated the importance of miR-1291 in targeting MUC1 for the regulation of esophagus cancer growth, invasion and apoptosis, and may be helpful for developing new targets for early diagnosis or new therapeutic targets for ESCC.
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Affiliation(s)
- Hailan Luo
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Wentao Guo
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Fei Wang
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Yanjie You
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Jianguo Wang
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Xudong Chen
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Jihong Wang
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Yuanyuan Wang
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yuwen Du
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xiaonan Chen
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Changgui Xue
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Guohua Song
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
| | - Fuqing Wang
- Department of Basic Medical Sciences, Luohe Medical College, Luohe, Henan 462002, P.R. China
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Huang C, Cao L, Qiu L, Dai X, Ma L, Zhou Y, Li H, Gao M, Li W, Zhang Q, Han K, Lv H. Upregulation of H19 promotes invasion and induces epithelial-to-mesenchymal transition in esophageal cancer. Oncol Lett 2015; 10:291-296. [PMID: 26171017 DOI: 10.3892/ol.2015.3165] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 03/24/2015] [Indexed: 01/01/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have previously been reported to be involved in cancer invasion, proliferation and apoptosis. However, the association between the lncRNA, H19, and esophageal cancer (EC) has remained elusive. In the present study, reverse transcription quantitative-polymerase chain reaction revealed that the expression of H19 was significantly increased and associated with tumor depth and metastasis in 133 EC samples. Furthermore, MTT and Transwell assays revealed that overexpression of H19 in vitro promoted the proliferation and invasion of EC cell lines, whereas knockdown of H19 inhibited the proliferation and invasion of EC cell lines. In addition, it was identified that an upregulation of H19 induced epithelial-to-mesenchymal transition, while the opposite effect was observed following the downregulation of H19. In conclusion, H19 has a significant role in the development of EC and may serve as a potential prognostic marker and therapeutic target for EC.
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Affiliation(s)
- Cheng Huang
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Lihua Cao
- Department of Dermatology, Yancheng City No. 1 People's Hospital, The Fourth Affiliated Hospital of Nantong Medical College, Yancheng, Jiangsu 224005, P.R. China
| | - Limin Qiu
- Department of Thoracic Surgery, Yancheng City No. 1 People's Hospital, The Fourth Affiliated Hospital of Nantong Medical College, Yancheng, Jiangsu 224005, P.R. China
| | - Xiaoli Dai
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Linwei Ma
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Yingting Zhou
- Department of Pathology, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Huifen Li
- Department of Pathology, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Min Gao
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Weiyong Li
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Qing Zhang
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Koulan Han
- Department of Clinical Medicine, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Hongzhen Lv
- Department of Pathology, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
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