miRNA-7/21/107 contribute to HBx-induced hepatocellular carcinoma progression through suppression of maspin

// Wen-Shu Chen 1, 2, 4, * , Chia-Jui Yen 6, * , Yun-Ju Chen 7, 8 , Jhen-Yu Chen 2, 4, 5 , Li-Yun Wang 2, 4 , Shu-Jun Chiu 9, 10 , Wen-Ling Shih 11 , Chien-Yi Ho 3 , Tzu-Tang Wei 1 , Hsiao-Lin Pan 7 , Pei-Hsuan Chien 7 , Mien-Chie Hung 2, 4, 12 , Ching-Chow Chen 1 , Wei-Chien Huang 2, 4, 5, 13 1 Department of Pharmacology, National Taiwan University, Taipei, Taiwan 2 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan 3 Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan 4 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 5 The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan 6 Internal Medicine, National Cheng-Kung University, Tainan, Taiwan 7 Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan 8 Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan 9 Department of Life Sciences, Tzu Chi University, Hualien, Taiwan 10 Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan 11 Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan 12 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 13 Department of Biotechnology, Asia University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Wei-Chien Huang, e-mail: whuang@mail.cmu.edu.tw Ching-Chow Chen, e-mail: chingchowchen@ntu.edu.tw Mien-Chie Hung, e-mail: mhung@mdanderson.org Keywords: HBx, microRNA, maspin, hepatocellular carcinoma cell, metastasis Received: May 19, 2015 Accepted: July 06, 2015 Published: July 17, 2015 ABSTRACT 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.