HBV suppresses ZHX2 expression to promote proliferation of HCC through miR-155 activation

Xiaojia Song, Siyu Tan, Zhuanchang Wu, Leiqi Xu, Zehua Wang, Yong Xu, Tixiao Wang, Chengjiang Gao, Yaoqin Gong, Xiaohong Liang, Lifen Gao, Brett T. Spear, Chunhong Ma

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were found in HBV-positive tumors, livers of HBV transgenic mice and HBx-overexpressing hepatoma cell lines. MiR-155 overexpression reduced ZHX2 levels via miR-155 seed sites in the ZHX2 3′UTR, whereas blocking miR-155 levels led to increased ZHX2 levels. Taken together, our data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC.

Original languageEnglish
Pages (from-to)3120-3130
Number of pages11
JournalInternational Journal of Cancer
Volume143
Issue number12
DOIs
StatePublished - Dec 15 2018

Bibliographical note

Publisher Copyright:
© 2018 UICC

Keywords

  • HBV
  • HCC
  • ZHX2
  • miR-155
  • proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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