Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2015; 21(42): 12150-12156
Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12150
Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy
Shogo Ohkoshi, Masahiko Yano, Yasunobu Matsuda
Shogo Ohkoshi, Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, Chuo-ku, Niigata 951-8580, Japan
Masahiko Yano, Yasunobu Matsuda, Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata 951-8520, Japan
Author contributions: Ohkoshi S wrote the paper; Yano M performed research; Matsuda Y analyzed the data.
Supported by Grant-in-Aid for Scientific Research (C) (22590722 for Ohkoshi S) from the Japan Society for the promotion of Science (JSPS).
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: Shogo Ohkoshi, MD, PhD, Professor of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, 1-8Hamaura-Cho, Chuo-ku, Niigata 951-8580, Japan.
Telephone: +81-25-2118243 Fax: +81-25-2671582
Received: March 30, 2015
Peer-review started: March 31, 2015
First decision: May 18, 2015
Revised: May 30, 2015
Accepted: August 31, 2015
Article in press: August 31, 2015
Published online: November 14, 2015

A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.

Keywords: p21, Tumor suppressors, Oncogene, Subcellular localization, Hepatocellular carcinoma, HBx, Nucleo-cytoplasmic export, Chromosome region maintenance 1, Selective inhibitors of nuclear export, Interferon

Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. These conflicting roles are reviewed in the context of the HBx gene and hepatocarcinogenesis. Because most tumor suppressors act in a similar manner to p21, regulation of their nucleo-cytoplasmic export, which is mainly effected via chromosome region maintenance 1, may be a basis for developing a new strategy for anti-hepatocellular carcinoma therapy.