Suppression of Maspin by IKKα-dependent MicroRNAs Confers HBx-mediated Hepatocellular Cancer Progression

• Main Authors: Wen-Shu Chen, 陳雯淑
• Other Authors: Ching-Chow Chen
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/8mt4ya

博士 === 國立臺灣大學 === 藥理學研究所 === 104 === 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 HBV X protein (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 were also correlated with maspin downregulation in HBV-associated HCC patients, and were associated with their poor overall survival. Our data further revealed that nuclear inhibitor-kB kinase-α (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 data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated nuclear IKKα as a critical regulator for HBx-mediated aggressiveness and chemoresistance in HCC, and suggested IKKα as a promising target to improve the therapeutic outcome of HCC patients.