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 language | English |
---|---|
Pages (from-to) | 3120-3130 |
Number of pages | 11 |
Journal | International Journal of Cancer |
Volume | 143 |
Issue number | 12 |
DOIs | |
State | Published - Dec 15 2018 |
Bibliographical note
Funding Information:Key words: ZHX2, miR-155, HBV, HCC, proliferation Abbreviations: HBV: hepatitis B virus; HCC: hepatocellular carcinoma; ZHX2: zinc fingers homeoboxes; NTCP: Na+-dependent taurocholate cotransporting polypeptide; PCNA: proliferating cell nuclear antigen Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors declare that they have no conflicts of interest. Grant sponsor: National Science Fund for Distinguished Young Scholars in China; Grant numbers: 81425012; Grant sponsor: National Key Research and Development Program; Grant numbers: 2016YFE0127000; Grant sponsor: National Natural Science Foundation of China; Grant numbers: 91529305, 81370527, 81702647; Grant sponsor: Natural Science Foundation of Shandong Province; Grant numbers: ZR2015HZ005, ZR201702190483, ZR2016HB16; Grant sponsor: Primary Research & Development Plan of Shandong Province; Grant numbers: 2016ZDJS07A17; Grant sponsor: Natural Science Foundation of Shandong Province; Grant sponsor: Primary Research & Development Plan of Shandong Province; Grant sponsor: National Natural Science Foundation of China DOI: 10.1002/ijc.31595 History: Received 10 Feb 2018; Accepted 3 May 2018; Online 11 May 2018 Correspondence to: Chunhong Ma, Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People’s Republic of China, Tel.: +86 531-883-82308, E-mail: machunhong@sdu.edu.cn; or Brett T. Spear, Department of Microbiology, Immunology and Molecular Genetics, Lexington, KY, Tel.: +1 859-257-5167, E-mail: bspear@uky.edu
Publisher Copyright:
© 2018 UICC
Keywords
- HBV
- HCC
- ZHX2
- miR-155
- proliferation
ASJC Scopus subject areas
- Oncology
- Cancer Research