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Phannasil P, Sukhuma C, Nauphar D, Nuamsee K, Svasti S. Up-regulation of microRNA 101-3p during erythropoiesis in β-thalassemia/HbE. Blood Cells Mol Dis 2023; 103:102781. [PMID: 37478523 DOI: 10.1016/j.bcmd.2023.102781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/18/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Ineffective erythropoiesis is the main cause of anemia in β-thalassemia. The crucial hallmark of ineffective erythropoiesis is the high proliferation of erythroblast. microRNA (miR/miRNA) involves several biological processes, including cell proliferation and erythropoiesis. miR-101 was widely studied and associated with proliferation in several types of cancer. However, the miR-101-3p has not been studied in β-thalassemia/HbE. Therefore, this study aims to investigate the expression of miR-101-3p during erythropoiesis in β-thalassemia/HbE. The results showed that miR-101-3p was upregulated in the erythroblast of β-thalassemia/HbE patients on day 7, indicating that miR-101-3p may be involved with high proliferation in β-thalassemia/HbE. Therefore, the mRNA targets of miR-101-3p including Rac1, SUB1, TET2, and TRIM44 were investigated to determine the mechanisms involved with high proliferation of β-thalassemia/HbE erythroblasts. Rac1 expression was significantly reduced at day 11 in severe β-thalassemia/HbE compared to normal controls and mild β-thalassemia/HbE. SUB1 gene expression was significantly lower in severe β-thalassemia/HbE compared to normal controls at day 9 of culture. For TET2 and TRIM44 expression, a significant difference was not observed among normal and β-thalassemia/HbE. However, the high expression of miR-101-3p at day 7 and these target genes was not correlated, suggesting that this miRNA may regulate ineffective erythropoiesis in β-thalassemia/HbE via other target genes.
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Affiliation(s)
- Phatchariya Phannasil
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Chanyanat Sukhuma
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Donny Nauphar
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand; Doctoral Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat 10430, Indonesia; Department of Genetics, Faculty of Medicine, Universitas Swadaya Gunung Jati, Cirebon 45132, West-Java, Indonesia
| | - Khanita Nuamsee
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
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Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
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Shen H, Ye F, Xu D, Fang L, Zhang X, Zhu J. The MYEOV-MYC association promotes oncogenic miR-17/93-5p expression in pancreatic ductal adenocarcinoma. Cell Death Dis 2021; 13:15. [PMID: 34930894 PMCID: PMC8688437 DOI: 10.1038/s41419-021-04387-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 12/21/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy worldwide. As metastasis and malignant progression are primarily responsible for the poor clinical outcomes of PDAC, identifying key genes involved in these processes and the underlying molecular mechanisms of PDAC is vital. In this study, by analyzing TCGA PDAC data and matched GTEx data, we found that MYEOV expression is associated with poor survival in PDAC patients and higher in carcinoma tissues than in healthy tissues. Elevated levels of MYEOV led to enhanced cell proliferation, invasion and migration in vitro and in vivo. Transcriptome analysis results revealed that MYEOV mediates global alterations in gene expression profiles in PDAC cells. MiRNA-seq analysis showed that MYEOV regulates the expression levels of miR-17-5p and miR-93-5p, and its depletion resulted in reduced cell proliferation, invasion and migration, as observed in MYEOV-knockdown PDAC cells. These effects are likely due to the ability of MYEOV to regulate enrichment of the transcription factor MYC at the gene promoter regions of the two miRNAs. Furthermore, we identified a complex containing MYEOV and MYC in the nucleus, providing additional evidence for the association of MYEOV with MYC. Taken together, our results suggest that MYEOV promotes oncogenic miR-17/93-5p expression by associating with MYC, contributing to PDAC progression.
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Affiliation(s)
- Hongzhang Shen
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fuqiang Ye
- Huadong Research Institute for Medicine and Biotechniques, Nanjing, China
| | - Dongchao Xu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liangliang Fang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Juanjuan Zhu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
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Wu H, Luo YX, Hu W, Zhao ML, Bie J, Yang M, Pan R, Huang NX, Feng G, Liu K, Song G. MicroRNA-382-5p inhibits osteosarcoma development and progression by negatively regulating VEZF1 expression. Oncol Lett 2021; 22:752. [PMID: 34539856 PMCID: PMC8436354 DOI: 10.3892/ol.2021.13013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 05/12/2021] [Indexed: 12/11/2022] Open
Abstract
Human osteosarcoma is the most frequent malignant primary bone tumor that mainly occurs in young adults and children. MicroRNAs (miRNAs/miRs) are abnormally expressed in human osteosarcoma and contribute to osteosarcoma initiation and development. The present study aimed to investigate the role of miR-382-5p in the nosogenesis of osteosarcoma and to identify a novel target for osteosarcoma treatment. miR-382-5p expression was detected in human osteosarcoma clinical tissues and cell lines, including 143B, U2OS and MG63, via reverse transcription-quantitative PCR analysis. Multiple bioinformatic prediction toowe used to identify the potential target genes of miR-382-5p and vascular endothelial zinc finger 1 (VEZF1), which were validated via the dual-luciferase reporter assay. MG63 and U2OS cells were transfected with miR-382-5p mimics. The Cell Counting Kit-8 assay was performed to assess cell proliferation, while the Transwell assay was performed to assess migration and invasion. Cell colony formation was measured via crystal violet staining, and apoptosis was assessed via Annexin V/propidium iodide staining. The wound healing assay was performed to assess the migratory ability of U2OS and MG63 cells. Antitumor effects of miR-382-5p were evaluated in nude mice xenografts using U2OS cells. The results demonstrated that miR-382-5p expression was markedly downregulated in human osteosarcoma tissues and cell lines compared with adjacent normal tissues. Transfection of miR-382-5p mimics into MG63 and U2OS cells significantly inhibited the malignant behaviors of cells, including decreased proliferation, migration, diminished colony formation and invasion, and promoted osteosarcoma cell apoptosis. Bioinformatics prediction indicated that VEZF1 is a direct target gene of miR-382-5p. Overexpression of VEZF1 restored osteosarcoma tumor development inhibited by miR-382-5p in vivo. In addition, overexpression of miR-382-5p restrained the growth of xenograft osteosarcoma in nude mice following co-transfection, and overexpression of VEZF1 attenuated the inhibitory effect of miR-382-5p in nude mice. miR-382-5p acted as a tumor suppressor gene and inhibited the malignant biological behaviors of human osteosarcoma cells and functions associated with directly targeting VEZF1. Taken together, these results suggest that the miR-382-5p/VEZF1 interaction has an important role in osteosarcoma development and progression, and thus may be used as a diagnostic and therapeutic target for osteosarcoma.
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Affiliation(s)
- Hui Wu
- Department of Orthopedics, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Yu-Xi Luo
- The First Clinical College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Wen Hu
- School of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Mao-Lin Zhao
- School of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jun Bie
- Oncology Department, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Mi Yang
- Oncology Department, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Rongqiang Pan
- Oncology Department, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Nan-Xiang Huang
- Department of Pediatric Surgery, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Gang Feng
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Kang Liu
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Guiqin Song
- School of Basic Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
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Yang A, Peng F, Zhu L, Li X, Ou S, Huang Z, Wu S, Peng C, Liu P, Kong Y. Melatonin inhibits triple-negative breast cancer progression through the Lnc049808-FUNDC1 pathway. Cell Death Dis 2021; 12:712. [PMID: 34272359 PMCID: PMC8285388 DOI: 10.1038/s41419-021-04006-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Melatonin has been reported to have tumor-suppressive effects via comprehensive molecular mechanisms, and long non-coding RNAs (lncRNAs) may participate in this process. However, the mechanism by which melatonin affects the function of lncRNAs in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is still unknown. Therefore, we aimed to investigate the differentially expressed mRNAs and lncRNAs in melatonin-treated TNBC cells and the interaction mechanisms. Microarray analyses were performed to identify differentially expressed mRNAs and lncRNAs in TNBC cell lines after melatonin treatment. To explore the functions and underlying mechanisms of the mRNAs and lncRNAs candidates, a series of in vitro experiments were conducted, including CCK-8, Transwell, colony formation, luciferase reporter gene, and RNA immunoprecipitation (RIP) assays, and mouse xenograft models were established. We found that after melatonin treatment, FUNDC1 and lnc049808 downregulated in TNBC cell lines. Knockdown of FUNDC1 and lnc049808 inhibited TNBC cell proliferation, invasion, and metastasis. Moreover, lnc049808 and FUNDC1 acted as competing endogenous RNAs (ceRNAs) for binding to miR-101. These findings indicated that melatonin inhibited TNBC progression through the lnc049808-FUNDC1 pathway and melatonin could be used as a potential therapeutic agent for TNBC.
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Affiliation(s)
- Anli Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Fu Peng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.,West China School of Pharmacy, Sichuan University, Chengdu, P. R. China
| | - Lewei Zhu
- Department of Breast Surgery, The First People's Hospital, Foshan, Guangdong, People's Republic of China
| | - Xing Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Shunling Ou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhongying Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Song Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Cheng Peng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.
| | - Peng Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
| | - Yanan Kong
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
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6
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Xie J, Zhou X, Wang R, Zhao J, Tang J, Zhang Q, Du Y, Pang Y. Identification of potential diagnostic biomarkers in MMPs for pancreatic carcinoma. Medicine (Baltimore) 2021; 100:e26135. [PMID: 34114996 PMCID: PMC8202616 DOI: 10.1097/md.0000000000026135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/05/2021] [Indexed: 02/02/2023] Open
Abstract
Pancreatic cancer (PC) is a malignant tumor which ranks fourth in cancer-related death. However, the specificity and sensitivity of traditional biomarkers such as carbohydrate antigen 19-9 no longer meet the clinical requirements.Tools as ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) were used to analyze the differential expression of matrix metalloproteinases (MMPs) in PC and adjacent tissues. For further analysis, we adopted database for annotation, visualization and integrated discovery (DAVID 6.8), transcriptional regulatory relationships unraveled by sentence-based text (TRRUST) and other tools. We also identified drugs targeted the selected MMPs.Eight MMPs (MMP1, MMP2, MMP7, MMP9, MMP11, MMP12, MMP14, and MMP28) were differentially expressed in PC and adjacent tissue. MMP1 (P = .0189), MMP7 (P = .000216), MMP11 (P = .0209), MMP14 (P = .00611) were correlated with the pathological stages of PC. Patients with higher expression of MMP1 (P = .0011), MMP2 (P = .011), MMP7 (P = .0081), MMP9 (P = .046), MMP11 (P = .0019), MMP12 (P = .0011), MMP14 (P = .0011), and MMP28 (P = 6.3e-06) showed poor prognosis. Ten transcription factors were associated with the up-regulation of selected MMPs. Marimastat (DB00786) was found to target selected MMPs.Our research revealed that selected MMPs played an important role in the early diagnosis and prognosis of PC.
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Affiliation(s)
- Junhao Xie
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
| | - Xianzhu Zhou
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
| | - Rui Wang
- Department of Chemistry & State Key Laboratory of Molecular Engineering of Polymers, Fudan University
| | - Jiulong Zhao
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
| | - Jian Tang
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
| | - Qichen Zhang
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
| | - Yiqi Du
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
- Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Yanan Pang
- Department of Gastroenterology, Changhai Hospital, Navy Medical University
- Shanghai Institute of Pancreatic Diseases, Shanghai, China
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7
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics. Clin Sci (Lond) 2021; 135:847-864. [PMID: 33755094 DOI: 10.1042/cs20201500] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/09/2021] [Accepted: 03/23/2021] [Indexed: 01/22/2023]
Abstract
Metastasis is the main cause of poor postoperative survival of hepatocellular carcinoma (HCC) patients. Cytoskeleton rearrangement is a key event in cancer metastasis. However, the significance of microtubule (MT), one of the core components of cytoskeleton, in this process is only beginning to be revealed. Here, we find that the MT dynamics regulator end-binding protein 2 (EB2) is highly expressed in HCC and predicts poor prognosis of HCC patients. Functional studies show that EB2 overexpression promotes HCC proliferation, invasion and metastasis in vitro and in vivo, while EB2 knockdown has opposite results. Mechanistically, EB2 mediates MTs destabilization, increases Src (Src proto-oncogene non-receptor tyrosine kinase) activity, and thus facilitates extracellular signal-regulated kinase (ERK) signaling activation, which could in turn promote EB2 expression in HCC, eventually resulting in enhanced HCC proliferation, invasion and metastasis. Furthermore, U0126, a specific ERK inhibitor, could effectively inhibit EB2-mediated HCC proliferation and metastasis in vitro and in vivo. In conclusion, EB2 coordinates MT cytoskeleton and intracellular signal transduction, forming an EB2-MT-ERK positive feedback loop, to facilitate HCC proliferation, invasion and metastasis. EB2 could serve as a promising prognostic biomarker and potential therapeutic target for HCC; HCC patients with high EB2 expression may benefit from treatment with ERK inhibitors.
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9
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Zhang S, Cheng Z, Wang Y, Han T. The Risks of miRNA Therapeutics: In a Drug Target Perspective. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:721-733. [PMID: 33654378 PMCID: PMC7910153 DOI: 10.2147/dddt.s288859] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/12/2020] [Indexed: 12/18/2022]
Abstract
RNAi therapeutics have been growing. Patisiran and givosiran, two siRNA-based drugs, were approved by the Food and Drug Administration in 2018 and 2019, respectively. However, there is rare news on the advance of miRNA drugs (another therapeutic similar to siRNA drug). Here we report the existing obstacles of miRNA therapeutics by analyses for resources available in a drug target perspective, despite being appreciated when it began. Only 10 obtainable miRNA drugs have been in clinical trials with none undergoing phase III, while over 60 siRNA drugs are in complete clinical trial progression including two approvals. We mechanically compared the two types of drug and found that their major distinction lay in the huge discrepancy of the target number of two RNA molecules, which was caused by different complementary ratios. One miRNA generally targets tens and even hundreds of genes. We named it “too many targets for miRNA effect” (TMTME). Further, two adverse events from the discontinuation of two miRNA therapeutics were exactly answered by TMTME. In summary, TMTME is inevitable because of the special complementary approach between miRNA and its target. It means that miRNA therapeutics would trigger a series of unknown and unpreventable consequences, which makes it a considerable alternative for application.
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Affiliation(s)
- Song Zhang
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.,College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Zhujun Cheng
- Department of Burn, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Yanan Wang
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Tianyu Han
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
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10
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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11
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Gupta M, Chandan K, Sarwat M. Role of microRNA and Long Non-Coding RNA in Hepatocellular Carcinoma. Curr Pharm Des 2020; 26:415-428. [PMID: 31939724 PMCID: PMC7403690 DOI: 10.2174/1381612826666200115093835] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 12/04/2019] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for about 80-90% of all liver cancers and is found to be the third most common cause of cancer mortality in the Asia-Pacific region. Risk factors include hepatitis B and C virus, cirrhosis, aflatoxin-contaminated food, alcohol, and diabetes. Surgically removing the tumor tissue seems effective but a high chance of recurrence has led to an urgent need to develop novel molecules for the treatment of HCC. Clinical management with sorafenib is found to be effective but it is only able to prolong survival for a few months. Various side effects like gastrointestinal and abdominal pain, hypertension, and hemorrhage are also associated with sorafenib, which calls for the unmet need of effective therapies against HCC. Similarly, the genetic mechanisms behind the occurrence of HCC are still unknown and need to be expounded further for developing newer candidates. Since unearthing the concept of these variants, transcriptomics has revealed the role of non-coding RNAs (ncRNAs) in many cellular, physiological and pathobiological processes. They are also found to be widely associated and abundantly expressed in a variety of cancer. Aberrant expression and mutations are closely related to tumorigenesis and metastasis and hence are classified as novel biomarkers and therapeutic targets for the treatment of cancer, including HCC. Herein, this review summarises the relationship between ncRNAs and hepatocellular carcinoma.
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Affiliation(s)
- Meenakshi Gupta
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Kumari Chandan
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
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12
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Screening and identification of potential prognostic biomarkers in bladder urothelial carcinoma: Evidence from bioinformatics analysis. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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13
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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14
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Lin B, Xu J, Wang F, Wang J, Zhao H, Feng D. LncRNA XIST promotes myocardial infarction by regulating FOS through targeting miR-101a-3p. Aging (Albany NY) 2020; 12:7232-7247. [PMID: 32315985 PMCID: PMC7202499 DOI: 10.18632/aging.103072] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 03/24/2020] [Indexed: 12/14/2022]
Abstract
The purpose of this study was to reveal the hypothesis that lncRNA X inactive specific transcript (XIST) can participate in the regulation of cardiomyocyte apoptosis in neonatal mice cardiomyocytes (NMCMs) and myocardial infarction (MI) through targeting miR-101a-3p. NMCMs were isolated from neonatal C57BL/6 mice and anoxia was induced in hypoxic chamber. MTT assay and flow cytometry were used to determine proliferation and apoptosis respectively. The target relationship among XIST, miR-101a-3p and FOS was revealed by bioinformatic analysis, luciferase reporter assay, pull-down assay and RNA immunoprecipitation assay. The expression of XIST, miR-101a-3p, FOS and apoptosis-related proteins was determined by qRT-PCR or western blot. MI model was constructed to reveal the role of XIST. We found that XIST was up-regulated in NMCMs under anoxia condition. Moreover, XIST increased FOS expression by sponging miR-101a-3p in anoxia cells. Silencing XIST expression improved cell viability and suppressed apoptosis in vitro and inhibited myocardial infarction by reducing the level of c-FOS and apoptosis-related proteins in vivo. Our findings suggest that XIST is involved in MI, modulation of its level can be used as a new strategy or potential target in the treatment of myocardial infarction.
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Affiliation(s)
- Bin Lin
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jing Xu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Feng Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jiaxiang Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Hui Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Deguang Feng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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15
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Elhefnawi M, Salah Z, Soliman B. The Promise of miRNA Replacement Therapy for Hepatocellular Carcinoma. Curr Gene Ther 2019; 19:290-304. [DOI: 10.2174/1566523219666191023101433] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/25/2019] [Accepted: 10/09/2019] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate
94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of
noncoding RNAs, which exhibit decreased or inhibited expression in the case of carcinogenesis.
Therefore, the replacement of these molecules leads to post-transcriptional regulation of tens to hundreds
of oncogenic targets and limiting the tumor. Interestingly, there is a group of tumor silencer
miRNAs that have been highlighted in HCC and herein, our review will discuss the prominent examples
of these miRs in terms of their efficient delivery using vectors, nano-delivery systems, their successful
models either in vitro or in vivo and pre-clinical trials. Collectively, tumor suppressor miRNAs
can act as novel therapeutics for HCC and more studies should be directed towards these promising
therapeutics.
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Affiliation(s)
- Mahmoud Elhefnawi
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Zeinab Salah
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Bangly Soliman
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
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16
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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17
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Shi J, An G, Guan Y, Wei T, Peng Z, Liang M, Wang Y. miR-328-3p mediates the anti-tumor effect in osteosarcoma via directly targeting MMP-16. Cancer Cell Int 2019; 19:104. [PMID: 31043859 PMCID: PMC6477748 DOI: 10.1186/s12935-019-0829-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/15/2019] [Indexed: 11/10/2022] Open
Abstract
Background Increasing reports demonstrated that dysregulated expression of microRNAs (miRNAs) leads to the progression of various tumors. Previous studies revealed that miR-328-3p exhibited dysregulated expression in various types of tumors. However, its function and underlying mechanism in osteosarcoma (OS) are still unexplored. Methods The expression of miR-328-3p in the tissues and OS cell lines was detected by qRT-PCR analysis. The effects of miR-328-3p in the proliferation were analyzed by MTT assay. The proliferation and apoptosis of OS cells were examined by colony formation assay and TUNEL staining respectively. The migration and tumor formation ability of OS cells were measured by wound healing assay and xenograft in vivo mice assay. Furthermore, the regulatory roles of miR-328-3p/MMP16 were determined by western blot and luciferase reporter assay. Results The expression of miR-328-3p was significantly decreased in OS tissues and cell lines. Furthermore, overexpression of miR-328-3p inhibited the cell proliferation and migration, but promoted the apoptosis of OS cells in vitro. Moreover, the analysis in vivo showed that miR-328-3p effectively suppressed the formation of tumors. According to the results of western blot analysis and luciferase reporter assay, we identified matrix metalloproteinase-16 (MMP-16) acted as a direct target of miR-328-3p. Moreover, the expression level of MMP-16, which participates in the occurrence and development of many cancers, was negatively correlated with the miR-328-3p expression in OS cells. Conclusion miR-328-3p inhibited the proliferation, migration but accelerated the apoptosis of OS by directly inhibiting MMP-16. And miR-328-3p/MMP-16 axis may be one of the mechanisms of OS development and a novel potential method for the treatment of OS in clinic.
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Affiliation(s)
- Jianhui Shi
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China.,2Department of Orthopaedics, Heilongjiang Provincial Hospital, No. 82, Zhongshan Road, Harbin, 150036 Heilongjiang China
| | - Gang An
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
| | - Ying Guan
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
| | - Tianli Wei
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
| | - Zhibin Peng
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
| | - Min Liang
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
| | - Yansong Wang
- 1Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province China
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18
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Wang Y, Lyu L, Zhang X, Zhang J. Autotaxin is a novel target of microRNA-101-3p. FEBS Open Bio 2019; 9:707-716. [PMID: 30984544 PMCID: PMC6443858 DOI: 10.1002/2211-5463.12608] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/26/2019] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Autotaxin (ATX), a vital enzyme that generates lysophosphatidic acid (LPA), affects many biological processes, including tumorigenesis, via the ATX–LPA axis. In this study, we demonstrate that microRNA‐101‐3p (miR‐101‐3p), a well‐known tumor suppressor, downregulates ATX expression at the posttranscriptional level. We found that miR‐101‐3p inhibits ATX regulation by directly targeting a conserved sequence in the ATX mRNA 3′UTR. Moreover, we observed an inverse correlation between ATX and miR‐101‐3p levels in various types of cancer cells. ATX is highly expressed in several human cancers. Here, we verified that ATX expression is significantly inhibited by miR‐101‐3p in U87 and HCT116 cells. ATX downregulation contributed to the suppression of migration, invasion, and proliferation mediated by miR‐101‐3p; furthermore, the tumor‐suppressing activity of miR‐101‐3p was partially reduced by the addition of LPA in U87 cells. Our data suggest that ATX is a novel target of miR‐101‐3p.
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Affiliation(s)
- Yuqin Wang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Lin Lyu
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Xiaotian Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Junjie Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
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19
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Bioinformatics analysis to identify the key genes affecting the progression and prognosis of hepatocellular carcinoma. Biosci Rep 2019; 39:BSR20181845. [PMID: 30705088 PMCID: PMC6386764 DOI: 10.1042/bsr20181845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, which has poor outcome. The present study aimed to investigate the key genes implicated in the progression and prognosis of HCC. The RNA-sequencing data of HCC was extracted from The Cancer Genome Atlas (TCGA) database. Using the R package (DESeq), the differentially expressed genes (DEGs) were analyzed. Based on the Cluepedia plug-in in Cytoscape software, enrichment analysis for the protein-coding genes amongst the DEGs was conducted. Subsequently, protein–protein interaction (PPI) network was built by Cytoscape software. Using survival package, the genes that could distinguish the survival differences of the HCC samples were explored. Moreover, quantitative real-time reverse transcription-PCR (qRT-PCR) experiments were used to detect the expression of key genes. There were 2193 DEGs in HCC samples. For the protein-coding genes amongst the DEGs, multiple functional terms and pathways were enriched. In the PPI network, cyclin-dependent kinase 1 (CDK1), polo-like kinase 1 (PLK1), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), serum amyloid A1 (SAA1), and lysophosphatidic acid receptor 3 (LPAR3) were hub nodes. CDK1 interacting with PLK1 and FOS, and LPAR3 interacting with FOS and SAA1 were found in the PPI network. Amongst the 40 network modules, 4 modules were with scores not less than 10. Survival analysis showed that anterior gradient 2 (AGR2) and RLN3 could differentiate the high- and low-risk groups, which were confirmed by qRT-PCR. CDK1, PLK1, FOS, SAA1, and LPAR3 might be key genes affecting the progression of HCC. Besides, AGR2 and RLN3 might be implicated in the prognosis of HCC.
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20
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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Zhang X, Pan Y, Fu H, Zhang J. Nucleolar and Spindle Associated Protein 1 (NUSAP1) Inhibits Cell Proliferation and Enhances Susceptibility to Epirubicin In Invasive Breast Cancer Cells by Regulating Cyclin D Kinase (CDK1) and DLGAP5 Expression. Med Sci Monit 2018; 24:8553-8564. [PMID: 30476929 PMCID: PMC6278864 DOI: 10.12659/msm.910364] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 06/11/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Differentially expressed genes (DEGs) of IBC were selected from the Gene Expression Omnibus (GEO) chip data: GSE21422 and GSE21974. Network analysis of the DEGs and IBC-related genes was performed in STRING database to find the core gene. Thus, this study aimed to determine the role of NUSAP1 in invasive breast cancer (IBC) and to investigate its effect on drug susceptibility to epirubicin (E-ADM). MATERIAL AND METHODS The mRNA expression of NUSAP1 was determined by quantitative polymerase chain reaction (q-PCR). The protein expression was detected by Western blotting. Cell growth and growth cycle were detected by MTT assay and flow cytometry, respectively. Cell migration and invasion were tested by Transwell assay. RESULTS Through use of gene network analysis, we found that NUSAP1 interacts with IBC-related genes. NUSAP1 presented high expression in IBC tissue samples and MCF-7 cells. NUSAP1 overexpression promoted the growth, migration, and invasion of MCF-7 cells. While NUSAP1 gene silencing downregulated the expression of genes associated with cell cycle progression in G2/M phase, cyclin D kinase (CDK1) and DLGAP5 arrested cells in G2/M phase and significantly inhibited the growth, migration, and invasion of MCF-7 cells. si-NUSAP1 increased the susceptibility of MCF-7 cells to E-ADM-induced apoptosis. CONCLUSIONS Our study provides evidence that downregulation of NUSAP1 can inhibit the proliferation, migration, and invasion of IBC cells by regulating CDK1 and DLGAP5 expression and enhances the drug susceptibility to E-ADM.
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22
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Wang C, Su K, Zhang Y, Zhang W, Chu D, Zhao Q, Guo R. MicroRNA-365 targets multiple oncogenes to inhibit proliferation, invasion, and self-renewal of aggressive endometrial cancer cells. Cancer Manag Res 2018; 10:5171-5185. [PMID: 30464615 PMCID: PMC6215916 DOI: 10.2147/cmar.s174889] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background MicroRNA-365 (miR-365) has been reported to be a tumor suppressor miRNA. However, the role of miR-365 in progression of endometrial cancer (EC) has not been explored, in this study, we have found that re-expression of miRNA-365 inhibits cell proliferation, causes apoptosis and senescence. Materials and methods Overexpression of miR-365 attenuated cell migration and invasion, inhibited sphere-forming capacity, and enhanced the chemosensitivity to paclitaxel. In silico prediction tools identified the potential targets of miR-365. Results We identified EZH2 and FOS as targets of miR-365 and found that downregulating these genes imitated the tumor suppressive effect of miR-365. The outcomes of the study suggested that a reverse correlation existed between low miR-365 and overexpression of FOS and EZH2 in EC tissue specimens. Conclusion The study concludes that miR-365 acts as an important tumor suppressor and contributes by suppressing cell invasiveness, proliferation, and self-renewal in cancer cell lines by regulating multiple oncogenes. We establish that miR-365-EZH2/FOS pathway is an important target for treating EC.
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Affiliation(s)
- Chunfang Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Ke Su
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Yanyan Zhang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Weiwei Zhang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Danxia Chu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Qian Zhao
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,
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23
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Zhang L, Lv Z, Xu J, Chen C, Ge Q, Li P, Wei D, Wu Z, Sun X. Micro
RNA
‐134 inhibits osteosarcoma angiogenesis and proliferation by targeting the
VEGFA
/
VEGFR
1 pathway. FEBS J 2018; 285:1359-1371. [PMID: 29474747 DOI: 10.1111/febs.14416] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 01/31/2018] [Accepted: 02/19/2018] [Indexed: 12/16/2022]
Affiliation(s)
| | - Zhi Lv
- Department of Orthopaedics The Second Hospital of Shanxi Medical University Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair Taiyuan China
| | - Jing Xu
- Shanxi Medical University Taiyuan China
| | | | | | - Pengcui Li
- Department of Orthopaedics The Second Hospital of Shanxi Medical University Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair Taiyuan China
| | | | - Zhuangzhuang Wu
- Department of Orthopaedics The Second Hospital of Shanxi Medical University Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair Taiyuan China
| | - Xiaojuan Sun
- Department of Orthopaedics The Second Hospital of Shanxi Medical University Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair Taiyuan China
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24
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Jiang X, Hao Y. Analysis of expression profile data identifies key genes and pathways in hepatocellular carcinoma. Oncol Lett 2018; 15:2625-2630. [PMID: 29434983 DOI: 10.3892/ol.2017.7534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 07/20/2017] [Indexed: 12/12/2022] Open
Abstract
The aims of the present study were to identify key genes and pathways associated with hepatocellular carcinoma (HCC) progression and predict compounds potentially associated with this type of carcinogenesis. The gene expression profile data of the GSE49515 dataset was obtained from the Gene Expression Omnibus database. The limma software package was used to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Biological Networks Gene Ontology tool and the Database for Annotation, Visualization and Integrated Discovery, respectively. The Michigan Molecular Interactions database plugin within the Cytoscape software platform was used to perform protein-protein interaction (PPI) network analysis. Chemical-gene interaction data for HCC were obtained from the Comparative Toxicogenomics Database to evaluate the associations between drugs and specific genes. A total of 302 DEGs, including 231 downregulated and 71 upregulated, were identified. Cytokine-cytokine receptor interaction and chemokine signaling were the significantly enriched pathways. Additionally, PPI network analysis indicated a total of 13 highest degree hub nodes, including FBJ murine osteosarcoma viral oncogene homolog (FOS) and DNA damage-inducible transcript 3 protein (DDIT3). Chemical-gene interaction analysis revealed that FUN and FOS were targeted by >500 compounds, while >200 genes were targeted by 2,3,7,8-tetrachlorodibenzodioxin and benzo(α)pyrene. In conclusion, the present study demonstrated that FOS, DDIT3, the cytokine-cytokine receptor interaction pathway and the chemokine signaling pathway may be key genes and pathways associated with the development of HCC. Furthermore, exposure to 2,3,7,8-tetrachlorodibenzodioxin or benzo(α)pyrene may lead to hepatocarcinogenesis.
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Affiliation(s)
- Xuwei Jiang
- Department of General Surgery, Shanghai, Baoshan District Hospital of Integrated Traditional and Western Medicine, Shanghai 201900, P.R. China
| | - Yuqing Hao
- Department of General Surgery, Shanghai, Baoshan District Hospital of Integrated Traditional and Western Medicine, Shanghai 201900, P.R. China
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25
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Wu Z, Zeng Q, Cao K, Sun Y. Exosomes: small vesicles with big roles in hepatocellular carcinoma. Oncotarget 2018; 7:60687-60697. [PMID: 27463001 PMCID: PMC5312412 DOI: 10.18632/oncotarget.10807] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
Despite improvements in the diagnosis and treatment of hepatocellular carcinoma (HCC), the prognosis is still poor. Pioneering work has demonstrated a potential role for tumour cell-derived exosomes (TEXs) in HCC. TEXs can mediate immune responses, antigen presentation and intracellular communication by serving as vehicles for the transfer of proteins, viruses, lipids and RNA between cells. An improved understanding of the roles played by exosomes could lead to a powerful new strategy for preventing and treating HCC. In this review, we summarise current understanding on the topic. The literature points to two faces of TEXs in HCC: 1) They can promote invasion, metastasis, immune evasion and modulation and 2) they can act as diagnostic and prognostic biomarkers, and can be used in anti-cancer drug resistance and immunotherapy in the future.
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Affiliation(s)
- Zhitong Wu
- Department of Clinical Laboratory, Eighth Affiliated Hospital of Guangxi Medical University, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Qinghai Zeng
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yifan Sun
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou, Guangxi, China
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26
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Pan JH, Zhou H, Zhao XX, Ding H, Li W, Qin L, Pan YL. Role of exosomes and exosomal microRNAs in hepatocellular carcinoma: Potential in diagnosis and antitumour treatments (Review). Int J Mol Med 2018; 41:1809-1816. [PMID: 29328436 PMCID: PMC5810235 DOI: 10.3892/ijmm.2018.3383] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 01/03/2018] [Indexed: 02/06/2023] Open
Abstract
Communication between hepatocellular carcinoma (HCC) cells and their environment is essential for the development and progression of HCC. Exosomes, which are microvesicles secreted by a number of cell types, are carriers of intercellular information and regulate the tumour microenvironment. Studies have demonstrated that exosomes are involved in the communication between HCC cells, endothelial cells and stem cells, and that they serve important roles in the metastasis and invasion, immune evasion and immunotherapy of HCC. In addition, the mechanism of HCC-derived exosome-mediated microRNA (miRNA) transfer is important in the environmental modulation of HCC growth and progression. As exosomes can be used for detecting and monitoring HCC, they can potentially serve as specific biomarkers for early-stage tumours and the tumour metastasis of HCC. Moreover, mesenchymal stem cell-derived exosomes can be transfected with miRNAs to inhibit HCC development. Therefore, as nucleic acid delivery vehicles, exosomes show a tremendous potential for effective treatment against HCC. In the present review, recent advances in our understanding of the source, composition and function of exosomes in HCC, and their potential value in the early diagnosis and treatment of HCC, are summarized.
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Affiliation(s)
- Jing-Hua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Hong Zhou
- Department of Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiao-Xu Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wei Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Li Qin
- Department of Histology and Embryology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yun-Long Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
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27
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Yang X, Pang YY, He RQ, Lin P, Cen JM, Yang H, Ma J, Chen G. Diagnostic value of strand-specific miRNA-101-3p and miRNA-101-5p for hepatocellular carcinoma and a bioinformatic analysis of their possible mechanism of action. FEBS Open Bio 2017; 8:64-84. [PMID: 29321958 PMCID: PMC5757177 DOI: 10.1002/2211-5463.12349] [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: 03/19/2017] [Revised: 05/08/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023] Open
Abstract
There is accumulating evidence that miRNA might serve as potential diagnostic and prognostic markers for various types of cancer. Hepatocellular carcinoma (HCC) is the most common type of malignant lesion but the significance of miRNAs in HCC remains largely unknown. The present study aimed to establish the diagnostic value of miR-101-3p/5p in HCC and then further investigate the prospective molecular mechanism via a bioinformatic analysis. First, the miR-101 expression profiles and parallel clinical parameters from 362 HCC patients and 50 adjacent non-HCC tissue samples were downloaded from The Cancer Genome Atlas (TCGA). Second, we aggregated all miR-101-3p/5p expression profiles collected from published literature and the Gene Expression Omnibus and TCGA databases. Subsequently, target genes of miR-101-3p and miR-101-5p were predicted by using the miRWalk database and then overlapped with the differentially expressed genes of HCC identified by natural language processing. Finally, bioinformatic analyses were conducted with the overlapping genes. The level of miR-101 was significantly lower in HCC tissues compared with adjacent non-HCC tissues (P < 0.001), and the area under the curve of the low miR-101 level for HCC diagnosis was 0.925 (P < 0.001). The pooled summary receiver operator characteristic (SROC) of miR-101-3p was 0.86, and the combined SROC curve of miR-101-5p was 0.80. Bioinformatic analysis showed that the target genes of both miR-101-3p and miR-101-5p are involved in several pathways that are associated with HCC. The hub genes for miR-101-3p and miR-101-5p were also found. Our results suggested that both miR-101-3p and miR-101-5p might be potential diagnostic markers in HCC, and that they exert their functions via targeting various prospective genes in the same pathways.
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Affiliation(s)
- Xia Yang
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Yu-Yan Pang
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Rong-Quan He
- Department of Medical Oncology First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Peng Lin
- Department of Ultrasonography First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Jie-Mei Cen
- Department of Medical Oncology First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Hong Yang
- Department of Ultrasonography First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Jie Ma
- Department of Medical Oncology First Affiliated Hospital of Guangxi Medical University Nanning China
| | - Gang Chen
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning China
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28
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Bao RF, Shu YJ, Hu YP, Wang XA, Zhang F, Liang HB, Ye YY, Li HF, Xiang SS, Weng H, Cao Y, Wu XS, Li ML, Wu WG, Zhang YJ, Jiang L, Dong Q, Liu YB. miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma. Oncotarget 2017; 7:22339-54. [PMID: 26968949 PMCID: PMC5008364 DOI: 10.18632/oncotarget.7970] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 02/23/2016] [Indexed: 12/13/2022] Open
Abstract
Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-β-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-β-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.
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Affiliation(s)
- Run-Fa Bao
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yi-Jun Shu
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yun-Ping Hu
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu-An Wang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Fei Zhang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hai-Bin Liang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yuan-Yuan Ye
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huai-Feng Li
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Shan-Shan Xiang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hao Weng
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Cao
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiang-Song Wu
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Mao-Lan Li
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Wen-Guang Wu
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yi-Jian Zhang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lin Jiang
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qian Dong
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China
| | - Ying-Bin Liu
- Department and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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29
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Hassan N, Zhao JT, Sidhu SB. The role of microRNAs in the pathophysiology of adrenal tumors. Mol Cell Endocrinol 2017; 456:36-43. [PMID: 28007658 DOI: 10.1016/j.mce.2016.12.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 11/29/2016] [Accepted: 12/12/2016] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in a sequence-specific manner. Due to its association with an assortment of diseases, miRNAs have been extensively studied in the last decade. In this review, the current understanding of the role of miRNAs in the pathophysiology of adrenal tumors is discussed. The recent contributions of high-throughput miRNA profiling studies have identified miRNAs that have functional and molecular roles in adrenal tumorigenesis. With respect to the biological heterogeneity of adrenal tumors and the limitations of the current treatments, an improved understanding of miRNAs may hold potential diagnostic and therapeutic value to facilitate better clinical management.
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Affiliation(s)
- Nunki Hassan
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia; Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Australia
| | - Jing Ting Zhao
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia; Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Australia
| | - Stan B Sidhu
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia; Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Australia; University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia.
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30
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Shaker O, Alhelf M, Morcos G, Elsharkawy A. miRNA-101-1 and miRNA-221 expressions and their polymorphisms as biomarkers for early diagnosis of hepatocellular carcinoma. INFECTION GENETICS AND EVOLUTION 2017; 51:173-181. [PMID: 28366737 DOI: 10.1016/j.meegid.2017.03.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/27/2017] [Accepted: 03/28/2017] [Indexed: 02/07/2023]
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31
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Keshavarzi M, Sorayayi S, Jafar Rezaei M, Mohammadi M, Ghaderi A, Rostamzadeh A, Masoudifar A, Mirzaei H. MicroRNAs‐Based Imaging Techniques in Cancer Diagnosis and Therapy. J Cell Biochem 2017; 118:4121-4128. [DOI: 10.1002/jcb.26012] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 03/22/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Maryam Keshavarzi
- Department of Oral and Maxillofacial RadiologySchool of DentistryLorestan University of Medical SciencesKhorramabadIran
| | - Saba Sorayayi
- Faculty of MedicineDepartment of Clinical BiochemistryArdabil University of Medical SciencesArdabilIran
| | - Mohammad Jafar Rezaei
- Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of MedicineKurdistan University of Medical SciencesSanandajIran
| | - Mohsen Mohammadi
- Faculty of PharmacyDepartment of Pharmaceutical BiotechnologyLorestan University of Medical SciencesKhorramabadIran
| | - Amir Ghaderi
- Faculty of PharmacyDepartment of Pharmaceutical BiotechnologyTehran University of Medical ScienceTehranIran
| | - Ayoob Rostamzadeh
- Faculty of MedicineDepartment of Anatomy and NeuroscienceShahrekord University of Medical SciencesShahrekordIran
| | - Aria Masoudifar
- Department of Molecular BiotechnologyRoyan Institute for BiotechnologyCell Science Research CenterACECRIsfahanIran
| | - Hamed Mirzaei
- Department of Medical BiotechnologySchool of MedicineMashhad University of Medical SciencesMashhadIran
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32
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Xu F, Liao JZ, Xiang GY, Zhao PX, Ye F, Zhao Q, He XX. MiR-101 and doxorubicin codelivered by liposomes suppressing malignant properties of hepatocellular carcinoma. Cancer Med 2017; 6:651-661. [PMID: 28135055 PMCID: PMC5345655 DOI: 10.1002/cam4.1016] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 12/11/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022] Open
Abstract
MiR-101, an important tumor-suppressive microRNA (miRNA) in hepatocellular carcinoma (HCC), has been affirmed significantly downregulated in HCC and participated in promoting apoptosis, decreasing proliferation and invasiveness of HCC cells, as well as increasing sensitivity of chemotherapeutic drug. However, miR-101-based combination therapies with doxorubicin (DOX) are not reported yet. Recently, nanomaterials-based approaches, especially liposome formulations, have been approved for clinical use and seem to provide a great opportunity to codeliver therapeutic agents for cancer therapy. In this study, we have successfully prepared liposome (L) nanoparticles to efficiently deliver miR-101 and DOX to HCC cells simultaneously. The effects of codelivery system miR-101/doxorubicin liposome (miR-101/DOX-L) on tumor malignant phenotypes of HCC cells were evaluated through analyzing cell proliferation, colony formation, cell migration, cell invasion, cell apoptosis assay, and the expression of related genes. In subcutaneous xenografts developed by HCC cells, the inhibition of tumor growth was analyzed through gross morphology, growth curve, proliferation marker Ki-67, apoptosis signals, and the expression of related genes. These experiments demonstrated that miR-101/DOX-L inhibited tumor properties of liver cancer cells in vitro and in vivo through targeting correlative genes by combinatory role of miR-101 and DOX. In conclusion, our results indicated that liposome nanoparticle is a reliable delivery strategy to codeliver miR-101 and DOX simultaneously, and miR-101- and DOX-based combination therapy can result in significant synergetic antitumor effects in vivo and vitro.
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Affiliation(s)
- Fei Xu
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Zhi Liao
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang-Ya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng-Xuan Zhao
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Ye
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xing-Xing He
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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33
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Tang XR, Wen X, He QM, Li YQ, Ren XY, Yang XJ, Zhang J, Wang YQ, Ma J, Liu N. MicroRNA-101 inhibits invasion and angiogenesis through targeting ITGA3 and its systemic delivery inhibits lung metastasis in nasopharyngeal carcinoma. Cell Death Dis 2017; 8:e2566. [PMID: 28102841 PMCID: PMC5386386 DOI: 10.1038/cddis.2016.486] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/16/2016] [Accepted: 12/15/2016] [Indexed: 01/09/2023]
Abstract
Clinically, distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC), and the treatment outcome of metastatic NPC remains disappointing, so there is a pressing need to identify novel therapeutic strategies. In accordance with our previous microarray data, we found that miR-101 was downregulated in NPC clinical specimens and cell lines. Ectopic expression of miR-101 significantly suppressed NPC cell migration, invasion and angiogenesis in vitro and inhibited angiogenesis and metastasis in vivo using the chicken chorioallantoic membrane model. Furthermore, ITGA3 was identified and validated as a novel target of miR-101, and the restoration of ITGA3 expression potently rescued the suppressive effects of miR-101. In addition, NPC patients with high ITGA3 expression had poorer overall survival and distant metastasis-free survival than patients with low ITGA3 expression, and ITGA3 overexpression was an independent poor prognostic factor in NPC. More importantly, we demonstrated that the systemic delivery of lentivirus-mediated miR-101 abrogated the lung metastatic colonization formation of NPC cells without obvious toxicity. Our study elucidates the molecular mechanisms of miR-101/ITGA3 pathway in regulating NPC metastasis and angiogenesis, and the systemic delivery of miR-101 provides a potent evidence for the development of a novel microRNA-targeting anticancer strategy for NPC patients.
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Affiliation(s)
- Xin-Ran Tang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Xin Wen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Qing-Mei He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Ying-Qin Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Xian-Yue Ren
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Xiao-Jing Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Jian Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Ya-Qin Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Jun Ma
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
| | - Na Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, People's Republic of China
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34
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Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development. Hepatol Res 2017; 47:80-94. [PMID: 27138942 DOI: 10.1111/hepr.12737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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35
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Ezzat WM, Amr KS. Insights for hepatitis C virus related hepatocellular carcinoma genetic biomarkers: Early diagnosis and therapeutic intervention. World J Hepatol 2016; 8:1251-1261. [PMID: 27843535 PMCID: PMC5084054 DOI: 10.4254/wjh.v8.i30.1251] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/15/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
The current review explores the role of emerging molecular contributing factors in liver carcinogenesis on top of hepatitis C virus (HCV). Here we will try to discuss the role genetic and epigenetic factors in pathogenesis of hepatocellular carcinoma. Understanding the role of these factors will help in discovering the mystery of liver carcinogenesis on top of chronic HCV infection. Moreover, use of the studied molecular factors will provide the hepatologists with tailored diagnostic promising biomarkers and flatten the way for establishment of emerging molecular treatment based on exploring the molecular subscription of this aggressive liver cancer.
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Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance. Oncotarget 2016; 6:25093-108. [PMID: 26231037 PMCID: PMC4694817 DOI: 10.18632/oncotarget.4437] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 06/19/2015] [Indexed: 12/30/2022] Open
Abstract
microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079-2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057-1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC.
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37
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Pratedrat P, Sopipong W, Makkoch J, Praianantathavorn K, Chuaypen N, Tangkijvanich P, Payungporn S. Single Nucleotide Polymorphisms in miR-149 (rs2292832) and miR-101-1 (rs7536540) Are Not Associated with Hepatocellular Carcinoma in Thai Patients with Hepatitis B Virus Infection. Asian Pac J Cancer Prev 2016; 16:6457-61. [PMID: 26434859 DOI: 10.7314/apjcp.2015.16.15.6457] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
MicroRNAs directly and indirectly influence many biological processes such as apoptosis, cell maintenance, and immune responses, impacting on tumor genesis and metastasis. They modulate gene expression at the post- transcriptional level and are associated with progression of liver disease. Hepatocellular carcinoma (HCC) is a cancer which mostly occurs in males. There are many factors affect HCC development, for example, hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), co-infection, environmental factors including alcohol, aflatoxin consumption and host-related factors such as age, gender immune response, microRNA and single nucleotide polymorphisms (SNPs). Chronic infection with the hepatitis B virus is the major factor leading to HCC progression since it causes the liver injury. At present, there are many reports regarding the association of SNPs on miRNAs and the HCC progression. In this research, we investigated the role of miR- 149 (rs2292832) and miR-101-1 (rs7536540) with HCC progression in Thai population. The study included 289 Thai subjects including 104 HCC patients, 90 patients with chronic hepatitis B virus infection (CHB) and 95 healthy control subjects. The allele and genotype of rs2292832 and rs7536540 polymorphisms were determined by TaqMan real-time PCR assay. Our results revealed no significant association between miR-149 (rs2292832) and miR-101-1 (rs7536540) and the risk of HCC in our Thai population. However, this research is the first study of miR-149 (rs2292832) and miR-101-1 (rs7536540) in HCC in Thai populations and the results need to be confirmed with a larger population.
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Affiliation(s)
- Pornpitra Pratedrat
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Thailand E-mail :
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Abstract
MicroRNA molecules have a variety of roles in cellular development and proliferation processes, including normal osteogenesis. These effects are exerted through post-translational inhibition of target genes. Altered miRNA expression has been demonstrated in several cancers, both in the tumor tissue and in the peripheral circulation. This may influence carcinogenesis if the specific miRNA targets are encoded by tumor suppressor genes or oncogenes. To date, most research investigating the role of microRNAs and primary bone tumors has focused on osteosarcoma and Ewing sarcoma. Several microRNAs including the miR-34 family have been implicated in osteosarcoma tumorigenesis via effects on the Notch signaling pathway. Progression, invasion, and metastasis of osteosarcoma tumor cells is also influenced by microRNA expression. In addition, microRNA expression may affect the response to chemotherapy in osteosarcoma and thus hold potential for future use as either a prognostic indicator or a therapeutic target. The EWS-FLI1 fusion protein produced in Ewing sarcoma has been shown to induce changes in miRNA expression. MicroRNA expression profiling may have some potential for prediction of disease progression and survival in Ewing sarcoma. There is limited evidence to support a role for microRNAs in other primary bone tumors, either malignant or benign; however, early work is suggestive of involvement in chondrosarcoma, multiple osteochondromatosis, and giant cell tumors of bone.
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39
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Mizuguchi Y, Takizawa T, Yoshida H, Uchida E. Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review. Hepatol Res 2016; 46:391-406. [PMID: 26490438 DOI: 10.1111/hepr.12606] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. The primary risk factor for HCC is liver cirrhosis secondary to persistent infection with hepatitis B virus or hepatitis C virus. Although a number of cellular phenomena and molecular events have been reported to facilitate tumor initiation, progression and metastasis, the exact etiology of HCC has not yet been fully uncovered. miRNA, a class of non-coding RNA, negatively regulate post-transcriptional processes that participate in crucial biological processes, including development, differentiation, apoptosis and proliferation. In the liver, specific miRNA can be negative regulators of gene expression. Recent studies have uncovered the contribution of miRNA to cancer pathogenesis as they can function as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential value in the clinical management of patients with HCC as some miRNA may be used as prognostic or diagnostic markers. In this review, we summarize the current knowledge about the roles of miRNA in the carcinogenesis and progression of HCC.
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Affiliation(s)
| | | | - Hiroshi Yoshida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Eiji Uchida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
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40
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Transforming growth factor (TGF) β1 acted through miR-130b to increase integrin α5 to promote migration of colorectal cancer cells. Tumour Biol 2016; 37:10763-73. [DOI: 10.1007/s13277-016-4965-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/02/2016] [Indexed: 11/25/2022] Open
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41
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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42
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miR-421 is a diagnostic and prognostic marker in patients with osteosarcoma. Tumour Biol 2016; 37:9001-7. [DOI: 10.1007/s13277-015-4578-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 12/02/2015] [Indexed: 12/23/2022] Open
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43
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A PCR-Based Method to Construct Lentiviral Vector Expressing Double Tough Decoy for miRNA Inhibition. PLoS One 2015; 10:e0143864. [PMID: 26624995 PMCID: PMC4666662 DOI: 10.1371/journal.pone.0143864] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 11/09/2015] [Indexed: 01/12/2023] Open
Abstract
DNA vector-encoded Tough Decoy (TuD) miRNA inhibitor is attracting increased attention due to its high efficiency in miRNA suppression. The current methods used to construct TuD vectors are based on synthesizing long oligonucleotides (~90 mer), which have been costly and problematic because of mutations during synthesis. In this study, we report a PCR-based method for the generation of double Tough Decoy (dTuD) vector in which only two sets of shorter oligonucleotides (< 60 mer) were used. Different approaches were employed to test the inhibitory potency of dTuDs. We demonstrated that dTuD is the most efficient method in miRNA inhibition in vitro and in vivo. Using this method, a mini dTuD library against 88 human miRNAs was constructed and used for a high-throughput screening (HTS) of AP-1 pathway-related miRNAs. Seven miRNAs (miR-18b-5p, -101-3p, -148b-3p, -130b-3p, -186-3p, -187-3p and -1324) were identified as candidates involved in AP-1 pathway regulation. This novel method allows for an accurate and cost-effective generation of dTuD miRNA inhibitor, providing a powerful tool for efficient miRNA suppression in vitro and in vivo.
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44
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Konno Y, Dong P, Xiong Y, Suzuki F, Lu J, Cai M, Watari H, Mitamura T, Hosaka M, Hanley SJB, Kudo M, Sakuragi N. MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells. Oncotarget 2015; 5:6049-62. [PMID: 25153722 PMCID: PMC4171612 DOI: 10.18632/oncotarget.2157] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.
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Affiliation(s)
- Yosuke Konno
- Department of Gynecology, Hokkaido University, Sapporo, Japan; These authors contributed equally to this work
| | - Peixin Dong
- Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan; These authors contributed equally to this work
| | - Ying Xiong
- Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China; These authors contributed equally to this work
| | - Fumihiko Suzuki
- Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan; These authors contributed equally to this work
| | - Jiabin Lu
- Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Muyan Cai
- Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | | | | | | | - Sharon J B Hanley
- Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan
| | - Masataka Kudo
- Department of Gynecology, Hokkaido University, Sapporo, Japan
| | - Noriaki Sakuragi
- Department of Gynecology, Hokkaido University, Sapporo, Japan; Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan
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45
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Miao L, Wang L, Yuan H, Hang D, Zhu L, Du J, Zhu X, Li B, Wang R, Ma H, Chen N. MicroRNA-101 polymorphisms and risk of head and neck squamous cell carcinoma in a Chinese population. Tumour Biol 2015; 37:4169-74. [PMID: 26490987 DOI: 10.1007/s13277-015-4249-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/13/2015] [Indexed: 01/17/2023] Open
Abstract
MicroRNAs (miRNAs) play important roles in regulation of gene expressions and likely have involvement in cancer susceptibility and disease progression. MicroRNA-101 (miR-101) has been well established as a tumor suppressor, and aberrant expression of miR-101 levels has been previously reported in different malignancies including head and neck squamous cell carcinoma (HNSCC). However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in the susceptibility to HNSCC remains unclear. In this study, we genotyped 11 selected SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study including 576 HNSCC cases and 1552 cancer-free controls. For the main effect analysis, none of the 11 selected SNPs was associated with HNSCC risk. However, in the stratification analysis by tumor sites, rs578481 and rs705509 in pri-miR-101-1 were significantly associated with risk of oral squamous cell carcinoma (OSCC) (rs578481: adjusted odds ratio (OR) = 1.19, 95 % confidence interval (CI) 1.01-1.39, P = 0.036; rs705509: adjusted OR = 0.85, 95 % CI 0.73-0.98, P = 0.030). Furthermore, combined analysis of the two SNPs revealed that subjects carrying the risk alleles of rs578481 and rs705509 had increased risk of OSCC in a dose-response manner (P trend = 0.022). Compared with subjects carrying "0-2" risk alleles, subjects carrying "3-4" risk alleles presented a 1.38-fold increased risk of OSCC. In conclusion, our findings suggested that the SNPs rs578481 and rs705509 locating in pri-miR-101-1 may play a role in genetic susceptibility to OSCC, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis.
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Affiliation(s)
- Limin Miao
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
| | - Lihua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hua Yuan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
| | - Dong Hang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Longbiao Zhu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
| | - Jiangbo Du
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xun Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Bing Li
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
| | - Ruixia Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
| | - Hongxia Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
| | - Ning Chen
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China. .,Institute of Stomatology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing, People's Republic of China.
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46
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Chen SP, Liu BX, Xu J, Pei XF, Liao YJ, Yuan F, Zheng F. MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC Cancer 2015; 15:706. [PMID: 26471185 PMCID: PMC4608176 DOI: 10.1186/s12885-015-1738-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 10/08/2015] [Indexed: 12/15/2022] Open
Abstract
Background Increasing evidence indicates that Epithelial–mesenchymal transition (EMT) can be regulated by microRNAs (miRNAs). MiR-449a is a liver abundant miRNA. However, the role of miR-449a in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. Methods The expression levels of miR-449a were first examined in HCC cell lines and tumour tissues by real-time PCR. The in vitro and in vivo functional effect and underlying molecular mechanisms of miR-449a were examined further. Results In the present study, we found that miR-449a was significantly decreased in HCC cells and tissues, especially in those with the portal vein tumor thrombus. In HCC cell lines, stable overexpression of miR-449a was sufficient to inhibit cell motility in vitro, and pulmonary metastasis in vivo. In addition, ectopic overexpression of miR-449a in HCC cells promoted the expression of epithelial markers and reduced the levels of mesenchymal markers. Further studies revealed that the reintroduction of miR-449a attenuated the downstream signaling of Met, and consequently reduced the accumulation of Snail in cell nucleus by targeting the 3’-untranslated regions (3’-UTR) of FOS and Met. Conclusions Our data highlight an important role of miR-449a in the molecular etiology of HCC, and implicate the potential application of miR-449a in cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1738-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shu-Peng Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107, Yanjiang West Road, Guangzhou, 510120, China. .,The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, No. 651, Dongfeng Road East, Guangzhou, China.
| | - Bao-Xin Liu
- Department of orthopedics, Guangzhou hospital of traditional Chinese medicine, No. 16, Zhuji Road, Guangzhou, China.
| | - Jie Xu
- Department of Pathology, Guangdong Provincial People's Hospital, No.107, Zhongshan Er Road, Guangzhou, China.
| | - Xiao-Feng Pei
- Department of Radiation Oncology, the Fifth Affiliated Hospital, Sun Yat-sen University, No. 57, Meihua East Road, Zhuhai, China.
| | - Yi-Ji Liao
- The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, No. 651, Dongfeng Road East, Guangzhou, China.
| | - Feng Yuan
- Department of Breast Surgery, Hubei Provincial Cancer Hospital, No. 116, Zhuodaoquan South Road, Wuhan, China.
| | - Fang Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107, Yanjiang West Road, Guangzhou, 510120, China.
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Long Noncoding RNA MEG3 Interacts with p53 Protein and Regulates Partial p53 Target Genes in Hepatoma Cells. PLoS One 2015; 10:e0139790. [PMID: 26444285 PMCID: PMC4596861 DOI: 10.1371/journal.pone.0139790] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/17/2015] [Indexed: 12/13/2022] Open
Abstract
Maternally Expressed Gene 3 (MEG3) encodes a lncRNA which is suggested to function as a tumor suppressor. Previous studies suggested that MEG3 functioned through activation of p53, however, the functional properties of MEG3 remain obscure and their relevance to human diseases is under continuous investigation. Here, we try to illuminate the relationship of MEG3 and p53, and the consequence in hepatoma cells. We find that transfection of expression construct of MEG3 enhances stability and transcriptional activity of p53. Deletion analysis of MEG3 confirms that full length and intact structure of MEG3 are critical for it to activate p53-mediated transactivation. Interestingly, our results demonstrate for the first time that MEG3 can interact with p53 DNA binding domain and various p53 target genes are deregulated after overexpression of MEG3 in hepatoma cells. Furthermore, results of qRT-PCR have shown that MEG3 RNA is lost or reduced in the majority of HCC samples compared with adjacent non-tumorous samples. Ectopic expression of MEG3 in hepatoma cells significantly inhibits proliferation and induces apoptosis. In conclusion, our data demonstrates that MEG3 functions as a tumor suppressor in hepatoma cells through interacting with p53 protein to activate p53-mediated transcriptional activity and influence the expression of partial p53 target genes.
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48
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine. World J Hepatol 2015; 7:1530-1540. [PMID: 26085912 PMCID: PMC4462691 DOI: 10.4254/wjh.v7.i11.1530] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/22/2014] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.
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49
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Gao Y, Wang Y, Feng J, Feng G, Zheng M, Yang Z, Xiao Z, Lu Z, Ye L, Zhang X. A hairpin within YAP mRNA 3′UTR functions in regulation at post-transcription level. Biochem Biophys Res Commun 2015; 459:306-312. [DOI: 10.1016/j.bbrc.2015.02.106] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 02/18/2015] [Indexed: 12/26/2022]
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50
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MicroRNA-509-3p inhibits cancer cell proliferation and migration by targeting the mitogen-activated protein kinase kinase kinase 8 oncogene in renal cell carcinoma. Mol Med Rep 2015; 12:1535-43. [PMID: 25815776 DOI: 10.3892/mmr.2015.3498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 02/10/2015] [Indexed: 11/05/2022] Open
Abstract
microRNAs (miRNAs; miR) are a class of small non-coding RNA molecules, which are involved in the pathogenesis of human diseases through the negative regulation of gene expression. Previous studies have demonstrated that miR-509-3p is a novel miRNA associated with cell proliferation and migration in 786-O renal cell carcinoma (RCC) cells. However, the mechanism of action of miR-509-3p in RCC remains to be elucidated. The present study aimed to examine the functional role and mechanism of miR-509-3p in the development of RCC. The results demonstrated that the expression levels of miR-509-3p were downregulated in the 786-O and ACHN RCC cell lines compared with the normal tissues of 10 patients with RCC, as determined by reverse transcription-quantitative polymerase chain reaction. The mRNA expression levels of mitogen-activated protein kinase kinase kinase 8 (MAP3K8) were upregulated in the RCC cell lines. Functional investigations demonstrated that the overexpression of miR-509-3p inhibited the migration and proliferation of the RCC cells, as determined by wound scratch and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Luciferase reporter assays revealed that the overexpression of miR-509-3p reduced the transcriptional activity of MAP3K8. Furthermore, the present study demonstrated that the ectopic transfection of miR-509-3p led to a significant reduction in the mRNA and protein expression levels of MAP3K8 in the RCC cells. Finally, knockdown of MAP3K8 inhibited the migration and proliferation of the RCC cells. Therefore, the results of the present study demonstrated that the miR-509-3p RCC suppressor was a significant regulator of the MAP3K8 oncogene, suggesting that it may have a potential therapeutic role in the treatment of RCC.
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