Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2019; 25(32): 4715-4726
Published online Aug 28, 2019. doi: 10.3748/wjg.v25.i32.4715
Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis
Ran-Xu Zhu, Alfred Sze Lok Cheng, Henry Lik Yuen Chan, Dong-Ye Yang, Wai-Kay Seto
Ran-Xu Zhu, Dong-Ye Yang, Wai-Kay Seto, Department of Gastroenterology and Hepatology, The University of Hong Kong–Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
Alfred Sze Lok Cheng, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Henry Lik Yuen Chan, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Author contributions: Zhu RX and Cheng ASL conceived and designed the study; All authors provided material support; Zhu RX performed the experiments and collected the data; Zhu RX and Cheng ASL analyzed the data; Zhu RX wrote the manuscript; All authors reviewed the manuscript; Zhu RX and Cheng ASL revised the manuscript; Zhu RX and Chan HLY provided financial support; Cheng ASL and Chan HLY provided study supervision; All authors gave final approval of the version of the article to published.
Supported by the National Natural Science Foundation of China, No. 81702777; and Natural Science Foundation of Guangdong Province, No. 2015A030310053.
Institutional review board statement: The study was reviewed and approved by the University of Hong Kong-Shenzhen Hospital Ethics Committee.
Conflict-of-interest statement: No potential conflicts of interest ware disclosed.
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:
Corresponding author: Ran-Xu Zhu, MD, PhD, Doctor, Department of Gastroenterology and Hepatology, The University of Hong Kong–Shenzhen Hospital, No. 1 Haiyuan Road, Futian District, Shenzhen 518053, Guangdong Province, China.
Telephone: +86-755-86913333 Fax: +86-755-86913333
Received: March 28, 2019
Peer-review started: March 28, 2019
First decision: April 16, 2019
Revised: July 14, 2019
Accepted: July 19, 2019
Article in press: July 19, 2019
Published online: August 28, 2019

Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible growth arrest cell cycle, apoptosis, and cell survival. GAS2 protein is universally expressed in most normal tissues, particularly in the liver, but is depleted in some tumor tissues. However, the functional mechanisms of GAS2 in hepatocellular carcinoma (HCC) are not fully defined.


To investigate the function and mechanism of GAS2 in HCC.


GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting. Cell proliferation was analyzed by counting, MTS, and colony formation assays. Cell cycle analysis was performed by flow cytometry. Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.


GAS2 protein expression was lower in HCC than in normal tissues. Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53, while knockdown of GAS2 promoted the proliferation of hepatocytes (P < 0.05). Furthermore, GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells, particularly the elevation of sub G1 (P < 0.01). Apoptosis induced by GAS2 was dependent on p53, which was increased by etoposide addition. The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated, but became diminished upon downregulation of GAS2. In the clinic specimen, GAS2 was downregulated in more than 60% of HCCs. The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues (P < 0.05).


GAS2 plays a vital role in HCC cell proliferation and apoptosis, possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

Keywords: Growth arrest-specific gene 2, Cell cycle, Apoptosis, Hepatocellular carcinoma, p53-dependent signaling pathway

Core tip: This study elucidated the function and mechanism of growth arrest-specific gene 2 (GAS2) in hepatocellular carcinoma (HCC) progression. By overexpression and knockdown approaches, we found that GAS2 inhibited the proliferation of HCC with wild-type p53. The effects of GAS2 on the cell cycle and apoptosis were investigated by flow cytometry, Annexin V apoptosis, and western blot assay, respectively. GAS2 suppressed HCC proliferation by deregulating the cell cycle and p53-dependent apoptosis pathway. Thus, GAS2 is expected to be a promising anti-oncogene and potential therapeutic target in HCC with wild-type p53.