Oncotarget

Research Papers:

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

Jhen-Yu Chen _, Yun-Ju Chen, Chia-Jui Yen, Wen-Shu Chen and Wei-Chien Huang

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Oncotarget. 2016; 7:473-489. https://doi.org/10.18632/oncotarget.6337

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Abstract

Jhen-Yu Chen1,2,*, Yun-Ju Chen3,4,5,*, Chia-Jui Yen6, Wen-Shu Chen7, Wei-Chien Huang1,2,7,8

1The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan

2Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan

3Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan

4School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan

5Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan

6Internal Medicine, National Cheng-Kung University, Tainan, Taiwan

7Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan

8Department of Biotechnology, Asia University, Taichung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Wei-Chien Huang, e-mail: [email protected]

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.


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