Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2017; 23(18): 3252-3261
Published online May 14, 2017. doi: 10.3748/wjg.v23.i18.3252
Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B
Xuyang Wang, Naoki Oishi, Tetsuro Shimakami, Taro Yamashita, Masao Honda, Seishi Murakami, Shuichi Kaneko
Xuyang Wang, Naoki Oishi, Tetsuro Shimakami, Taro Yamashita, Masao Honda, Seishi Murakami, Shuichi Kaneko, Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Ishikawa, Japan
Naoki Oishi, Tetsuro Shimakami, Taro Yamashita, Masao Honda, Shuichi Kaneko, Department of Gastroenterology, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan
Author contributions: Wang X, Oishi N and Shimakami T designed the study and contributed to acquisition of data; Wang X, Oishi N and Yamashita T contributed to analysis and interpretation of data; Wang X and Oishi N contributed to drafting of the manuscript; Honda M, Murakami S and Kaneko S contributed to critical revision of the manuscript for important intellectual content; Wang X and Oishi N contributed to statistical analysis; Murakami S and Kaneko S are the guarantors of this study.
Supported by Grant-in-Aid for Scientific Research (KAKENHI) (C), No. 15K08992 (to Oishi N); and Core-to-Core Program, B. Asia-Africa Science Platforms, the Japan Society for the Promotion of Science (to Kaneko S).
Conflict-of-interest statement: To the best to our knowledge, no conflict of interest exists.
Data sharing statement: No additional data are available.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Naoki Oishi, MD, PhD, Researcher, Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Ishikawa, Japan. ooishi@m-kanazawa.jp
Telephone: +81-76-2652233 Fax: +81-76-2344250
Received: December 31, 2016
Peer-review started: January 3, 2017
First decision: February 9, 2017
Revised: February 28, 2017
Accepted: March 30, 2017
Article in press: March 30, 2017
Published online: May 14, 2017
Processing time: 134 Days and 13.7 Hours
Abstract
AIM

To determine the role of hepatitis B virus X protein (HBx), HBx in regulating hepatic progenitor cell (HPC)-like features in hepatocellular carcinoma (HCC) and the underlying molecular mechanisms.

METHODS

We used a retrovirus vector to introduce wild type HBx or empty vector into HepG2 cells. We then used these cells to analyze cell proliferation, senescence, transformation, and stem-like features. Gene expression profiling was carried out on Affymetrix GeneChip Human U133A2.0 ver.2 arrays according to the manufacturer’s protocol. Unsupervised hierarchical clustering analysis and Class Comparison analysis were performed by BRB-Array Tools software Version 4.2.2. A total of 238 hepatitis B virus (HBV)-related HCC patients’ array data were used for analyzing clinical features.

RESULTS

The histone demethylase KDM5B was significantly highly expressed in HBV-related HCC cases (P < 0.01). In HBV proteins, only HBx up-regulated KDM5B by activating c-myc. Hepatic stem cell (HpSC) markers (EpCAM, AFP, PROM1, and NANOG) were significantly highly expressed in KDM5B-high HCC cases (P < 0.01). KDM5B played an important role in maintaining HpSC-like features and was associated with a poor prognosis. Moreover, inhibition of KDM5B suppressed spheroid formation and cell invasion in vitro.

CONCLUSION

HBx activates the histone demethylase KDM5B and induces HPC-like features in HCC. Histone demethylases KDM5B may be an important therapeutic target against HBV-related HCC cases.

Keywords: Hepatitis B virus X protein; Hepatocellular carcinoma; KDM5B; Progenitor cell; Tumorigenesis

Core tip: The role of epigenetic regulation in cancer biology has been the subject of several studies. These chromatin structure modifiers have been increasingly shown to facilitate several steps of cancer progression. However, the epigenetic regulation of hepatocellular carcinoma has not been elucidated. We assumed that multifunctional protein hepatitis B virus X (HBx) protein, may affect epigenetic regulation of Hepatocellular carcinoma. We showed that HBx activated the histone demethylase KDM5B and induced HPC-like features in hepatocellular carcinoma (HCC) in this study. Our results suggested that histone demethylases may be an important therapeutic target against HBV-related HCC cases.