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

Jhen-Yu Chen; Yun-Ju Chen; Chia-Jui Yen; Wen-Shu Chen; Wei-Chien Huang

doi:10.18632/oncotarget.6337

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

Oncotarget. 2016 Jan 5;7(1):473-89. doi: 10.18632/oncotarget.6337.

Authors

Jhen-Yu Chen^{1

2}, Yun-Ju Chen^{3

4

5}, Chia-Jui Yen⁶, Wen-Shu Chen⁷, Wei-Chien Huang^{1

2

7

8}

Affiliations

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.

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.

Keywords: EGFR family; HBx; hepatocellular carcinoma; lapatinib; target therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / virology
Cell Cycle / drug effects
Cell Cycle / genetics
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Hep G2 Cells
Hepatitis B virus / genetics
Hepatitis B virus / metabolism
Hepatitis B virus / physiology
Humans
Lapatinib
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / virology
NF-kappa B / genetics
NF-kappa B / metabolism
Protein Kinase Inhibitors / pharmacology
Quinazolines / pharmacology*
RNA Interference
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Receptor, ErbB-3 / genetics
Receptor, ErbB-3 / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Trans-Activators / genetics
Trans-Activators / metabolism*
Up-Regulation / drug effects
Viral Regulatory and Accessory Proteins

Substances

NF-kappa B
Protein Kinase Inhibitors
Quinazolines
Trans-Activators
Viral Regulatory and Accessory Proteins
hepatitis B virus X protein
Lapatinib
ERBB2 protein, human
ERBB3 protein, human
ErbB Receptors
Receptor, ErbB-2
Receptor, ErbB-3