Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Oct 18, 2015; 7(23): 2459-2469
Published online Oct 18, 2015. doi: 10.4254/wjh.v7.i23.2459
Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma
Jun-ichi Takino, Kentaro Nagamine, Takamitsu Hori, Akiko Sakasai-Sakai, Masayoshi Takeuchi
Jun-ichi Takino, Kentaro Nagamine, Takamitsu Hori, Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima 737-0112, Japan
Akiko Sakasai-Sakai, Masayoshi Takeuchi, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan
Author contributions: All authors contributed to this study.
Supported by The Japan Society for the Promotion of Science (JSPS) KAKENHI, Grant No. 22300264 and No. 25282029 (to Takeuchi M); the Ministry of Education, Culture, Sports, Science; Technology (MEXT), Regional Innovation Strategy Support Program (to Takeuchi M); and Kanazawa Medical University, No. SR2012-04.
Conflict-of-interest statement: The authors declare no conflict of interest associated with this manuscript.
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: Masayoshi Takeuchi, PhD, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku, Ishikawa 920-0293, Japan.
Telephone: +81-76-2862211 Fax: +81-76-2863652
Received: March 18, 2015
Peer-review started: March 18, 2015
First decision: April 23, 2015
Revised: May 7, 2015
Accepted: August 29, 2015
Article in press: September 7, 2015
Published online: October 18, 2015

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.

Keywords: Hepatocellular carcinoma, Nonalcoholic steatohepatitis, Advanced glycation end-products, Toxic advanced glycation end-products, Receptor for advanced glycation end-products, Hepatic stellate cells

Core tip: Expression of the receptor for advanced glycation end-products (RAGE), which is a multi-ligand cell surface receptor, is correlated with the poor therapeutic outcomes and malignancy of hepatocellular carcinoma (HCC). The synthesis of toxic advanced glycation end-products (TAGE), ligands of RAGE, is increased in nonalcoholic steatohepatitis (NASH) as well as in NASH-related HCC. Interactions between TAGE and RAGE induce oxidative stress, which may, in turn, lead to adverse effects in tumor cells and hepatic stellate cells during NASH or NASH-related HCC progression. Therefore, these findings prompted us to suggest that the TAGE-RAGE axis may be a treatment target in NASH-related HCC.