Nuclear IKKα mediates microRNA-7/-103/107/21 inductions to downregulate maspin expression in response to HBx overexpression
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Wen-Shu Chen1,2,5, Liang-Chih Liu3,6, Chia-Jui Yen8, Yun-Ju Chen9,10, Jhen-Yu Chen2,5,7, Chien-Yi Ho4, Shu-Hui Liu11, Ching-Chow Chen1, Wei-Chien Huang2,5,7,12
1Department of Pharmacology, National Taiwan University, Taipei, Taiwan
2Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
3Division of Breast Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan
4Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
5Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
6School of Medicine, China Medical University, Taichung, Taiwan
7The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
8Internal Medicine, National Cheng-Kung University, Tainan, Taiwan
9Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan
10Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan
11Department of Health Care and Social Work, Yu Da University of Science and Technology, Miaoli, Taiwan
12Department of Biotechnology, Asia University, Taichung, Taiwan
Wei-Chien Huang, email: [email protected]
Keywords: IKKα, maspin, HBx, microRNA, hepatocellular carcinoma
Received: December 01, 2015 Accepted: June 15, 2016 Published: July 07, 2016
Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-κB kinase-α (IKKα) to promote HCC progression. In this study, our data further revealed that nuclear IKKα expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKβ reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKKα as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKKα as a promising target to improve the therapeutic outcome of HCC patients.
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