HBx sensitizes hepatocellular carcinoma cells to lapatinib by up-regulating ErbB3

// Jhen-Yu Chen 1, 2, * , Yun-Ju Chen 3, 4, 5, * , Chia-Jui Yen 6 , Wen-Shu Chen 7 , Wei-Chien Huang 1, 2, 7, 8 1 The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan 2 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 3 Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan 4 School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan 5 Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan 6 Internal Medicine, National Cheng-Kung University, Tainan, Taiwan 7 Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan 8 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 Keywords: HBx, hepatocellular carcinoma, EGFR family, lapatinib, target therapy Received: June 01, 2015      Accepted: November 06, 2015      Published: November 16, 2015 ABSTRACT Poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) involves HBV X protein (HBx)-induced tumor progression. HBx also contributes to chemo-resistance via inducing the expressions of anti-apoptosis and multiple drug resistance genes. However, the impact of HBx expression on the therapeutic efficacy of various receptor tyrosine kinase inhibitors remains unknown. In this study, our data showed that HBx overexpression did not alter the cellular sensitivity of HCC cell lines to sorafenib but unexpectedly enhanced the cell death induced by EGFR family inhibitors, including gefitinib, erlotinib, and lapatinib due to ErbB3 up-regulation. Mechanistically, HBx transcriptionally up-regulates ErbB3 expression in a NF-κB dependent manner. In addition, HBx also physically interacts with ErbB2 and ErbB3 proteins and enhances the formation of ErbB2/ErbB3 heterodimeric complex. The cell viability of HBx-overexpressing cells was decreased by silencing ErbB3 expression, further revealing the pivotal role of ErbB3 in HBx-mediated cell survival. Our data suggest that HBx shifts the oncogenic addiction of HCC cells to ErbB2/ErbB3 signaling pathway via inducing ErbB3 expression and thereby enhances their sensitivity to EGFR/ErbB2 inhibitors.