miRNA-7/21/107 contribute to HBx-induced hepatocellular carcinoma progression through suppression of maspin
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Wen-Shu Chen1,2,4,*, Chia-Jui Yen6,*, Yun-Ju Chen7,8, Jhen-Yu Chen2,4,5, Li-Yun Wang2,4, Shu-Jun Chiu9,10, Wen-Ling Shih11, Chien-Yi Ho3, Tzu-Tang Wei1, Hsiao-Lin Pan7, Pei-Hsuan Chien7, Mien-Chie Hung2,4,12, Ching-Chow Chen1, Wei-Chien Huang2,4,5,13
1Department of Pharmacology, National Taiwan University, Taipei, Taiwan
2Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
3Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
4Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
5The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
6Internal Medicine, National Cheng-Kung University, Tainan, Taiwan
7Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
8Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan
9Department of Life Sciences, Tzu Chi University, Hualien, Taiwan
10Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan
11Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan
12Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
13Department of Biotechnology, Asia University, Taichung, Taiwan
*These authors have contributed equally to this work
Wei-Chien Huang, e-mail: [email protected]
Ching-Chow Chen, e-mail: [email protected]
Mien-Chie Hung, e-mail: [email protected]
Keywords: HBx, microRNA, maspin, hepatocellular carcinoma cell, metastasis
Received: May 19, 2015 Accepted: July 06, 2015 Published: July 17, 2015
Maspin suppresses tumor progression by promoting cell adhesion and apoptosis and by inhibiting cell motility. However, its role in tumorigenesis of hepatocellular carcinoma (HCC) remains unclear. The gene regulation of maspin and its relationship with HCC patient prognosis were investigated in this study. Maspin expression was specifically reduced in HBV-associated patients and correlated with their poor prognosis. Maspin downregulation in HCC cells was induced by HBx to promote their motility and resistance to anoikis and chemotherapy. HBx-dependent induction of microRNA-7, -107, and -21 was further demonstrated to directly target maspin mRNA, leading to its protein downregulation. Higher expressions of these microRNAs also correlated with maspin downregulation in HBV-associated patients, and were associated with their poor overall survival. These data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated that downregulation of maspin by microRNAs confers HBx-mediated aggressiveness and chemoresistance in HCC.
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