Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2018; 24(32): 3650-3662
Published online Aug 28, 2018. doi: 10.3748/wjg.v24.i32.3650
Abnormal expression of HMGB-3 is significantly associated with malignant transformation of hepatocytes
Wen-Jie Zheng, Min Yao, Miao Fang, Li Wang, Zhi-Zhen Dong, Deng-Fu Yao
Wen-Jie Zheng, Miao Fang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Min Yao, Department of Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Li Wang, Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Zhi-Zhen Dong, Department of Diagnostics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Author contributions: Zheng WJ and Yao M contributed equally to this work and wrote the first draft; Fang M performed the cell experiments; Wang L analyzed data; Zheng WJ conducted the animal model study; Dong ZZ and Yao DF revised the manuscript. All authors approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 81673241 and No. 81702419; Projects of Jiangsu Medical Science, No. BE2016698; Jiangsu Graduate Innovation, No. KYCX17_1934; Nantong Health and Family Planning Commission, No. WQ2016083; and National Int S&T Cooperation Program, No. 2013DFA32150.
Institutional animal care and use committee statement: The study protocol was approved by the Animal Medical Ethics Committee of Affiliated Hospital of Nantong University.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional unpublished data are available.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: Deng-Fu Yao, MD, PhD, Professor, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Nantong 226001, Jiangsu Province, China. yaodf@ahnmc.com
Telephone: +86-513-85052523
Received: May 18, 2018
Peer-review started: May 19, 2018
First decision: June 6, 2018
Revised: June 14, 2018
Accepted: June 27, 2018
Article in press: June 27, 2018
Published online: August 28, 2018
Abstract
AIM

To explore the relationship between dynamic expression of high mobility group box-3 (HMGB3) and malignant transformation of hepatocytes.

METHODS

Expression of HMGB family proteins were observed in rat hepatocarcinogenesis models induced with 2-acetylaminofluorene. Alterations of HMGB3 were analyzed at the mRNA level by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and at the protein level by immunohistochemistry or Western blotting. HMGB3 in human liver cancer tissues were evaluated using bioinformatics databases from GEO, TCGA, and Oncomine. A specific HMGB3-shRNA was used to knock down HMGB3 expression in order to investigate its effects on proliferation and cell cycle in vitro and in vivo.

RESULTS

Elevated HMGB3 levels were first reported in hepatocarcinogenesis, with increasing expression from normal liver to cancer. Bioinformatic databases showed that HMGB3 expression in hepatocellular carcinoma tissues was significantly higher than that in normal liver tissues. Higher HMGB3 expression was discovered in liver cancer cells compared with LO2 cells in vitro. According to gene set enrichment analysis, HMGB3 mRNA levels were correlated with cell cycle and DNA replication pathways. Knocking down HMGB3 by specific shRNA significantly inhibited proliferation of HepG2 cells by cell cycle arrest and downregulating DNA replication related genes (cyclin B1, FEN1, and PCNA) at the mRNA and protein level. Furthermore, silencing HMGB3 significantly inhibited xenograft tumor growth (measured by Ki67) in vivo.

CONCLUSION

HMGB3 is involved in malignant transformation of hepatocytes and could be a useful biomarker for diagnosis and a potential target for therapy of liver cancer.

Keywords: Liver cancer, HMGB-3, Hepatocarcinogenesis, Proliferation, Tumor growth

Core tip: High mobility group box (HMGB) family proteins were correlated with hepatocellular carcinoma (HCC) development and progression. This current study examined the effects of HMGB3 on HCC both in vitro and in vivo. Overexpression of HMGB3 was observed in hepatic malignant transformation and HCC tissues in bioinformatic databases. Knockdown of HMGB3 significantly inhibited proliferation, cell cycle, and tumor growth of HCC cells, providing a novel insight for HCC research.