Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 8, 2016; 8(25): 1061-1066
Published online Sep 8, 2016. doi: 10.4254/wjh.v8.i25.1061
Inhibition of apoptosis by oncogenic hepatitis B virus X protein: Implications for the treatment of hepatocellular carcinoma
Chuck C K Chao
Chuck C K Chao, Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
Chuck C K Chao, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
Chuck C K Chao, Chang Gung Memorial Hospital at Linkuo, Liver Research Center, Taoyuan 33305, Taiwan
Author contributions: The author solely contributed to this paper.
Conflict-of-interest statement: No conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Chuck C K Chao, PhD, Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist, Taoyuan 33302, Taiwan.
Telephone: +886-32-118800-5151 Fax: +886-32-118700
Received: April 21, 2016
Peer-review started: April 22, 2016
First decision: June 6, 2016
Revised: June 27, 2016
Accepted: July 20, 2016
Article in press: July 22, 2016
Published online: September 8, 2016

Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). In addition, hepatoma upregulated protein (HURP) is a cellular oncogene that is upregulated in a majority of HCC cases. We highlight here recent findings demonstrating a link between HBx, HURP and anti-apoptosis effects observed in cisplatin-treated HCC cells. We observed that Hep3B cells overexpressing HBx display increased HURP mRNA and protein levels, and show resistance to cisplatin-induced apoptosis. Knockdown of HURP in HBx-expressing cells reverses this effect, and sensitizes cells to cisplatin. The anti-apoptotic effect of HBx requires activation of the p38/MAPK pathway as well as expression of SATB1, survivin and HURP. Furthermore, silencing of HURP using short-hairpin RNA promotes accumulation of p53 and reduces cell proliferation in SK-Hep-1 cells (p53+/–), whereas these effects are not observed in p53-mutant Mahlavu cells. Similarly, HURP silencing does not affect the proliferation of H1299 lung carcinoma cells or Hep3B HCC cells which lack p53. Silencing of HURP sensitizes SK-Hep-1 cells to cisplatin. While HURP overexpression promotes p53 ubiquitination and degradation by the proteasome, HURP silencing reverses these effects. Inoculation of SK-Hep-1 cancer cells in which HURP has been silenced produces smaller tumors than control in nude mice. Besides, gankyrin, a positive regulator of the E3 ubiquitin ligase MDM2, is upregulated following HURP expression, and silencing of gankyrin reduces HURP-mediated downregulation of p53. In addition, we observed a positive correlation between HURP and gankyrin protein levels in HCC patients (r2 = 0.778; n = 9). These findings suggest a role for the viral protein HBx and the host protein HURP in preventing p53-mediated apoptosis during cancer progression and establishment of chemoresistance.

Keywords: Hepatitis B virus X protein, Hepatocellular carcinoma, Hepatitis B virus, Hepatoma upregulated protein, p53, Gankyrin, SATB1

Core tip: Hepatitis B virus X protein (HBx) plays a critical role in the development of hepatocellular carcinoma (HCC). Hepatoma upregulated protein (HURP) is an oncogene that is upregulated in a majority of HCC cases. However, the role of these proteins in the response of HCC cells to chemotherapeutic drugs remains unclear. We show here that the HBx/SATB1/HURP axis plays a critical role in down-regulating p53 and upregulating anti-apoptotic proteins in vitro and in vivo. We discuss the regulation of this novel pathway and its implications in resistance of HCC cells to chemotherapy.