Retrospective Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2016; 22(33): 7569-7578
Published online Sep 7, 2016. doi: 10.3748/wjg.v22.i33.7569
Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication
Ayato Murata, Takuya Genda, Takafumi Ichida, Nozomi Amano, Sho Sato, Hironori Tsuzura, Shunsuke Sato, Yutaka Narita, Yoshio Kanemitsu, Yuji Shimada, Katsuharu Hirano, Katsuyori Iijima, Ryo Wada, Akihito Nagahara, Sumio Watanabe
Ayato Murata, Takuya Genda, Nozomi Amano, Sho Sato, Hironori Tsuzura, Shunsuke Sato, Yutaka Narita, Yoshio Kanemitsu, Yuji Shimada, Katsuyori Iijima, Akihito Nagahara, Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan
Takafumi Ichida, Katsuharu Hirano, Department of Hepatology, Shonan-East General Hospital, Kanagawa 253-0083, Japan
Ryo Wada, Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan
Sumio Watanabe, Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8431, Japan
Author contributions: Murata A, Genda T, Ichida T, Amano N, Sato S, Tsuzura H, Sato S, Narita Y, Kanemitsu Y, Shimada Y, Hirano K, Iijima K, Wada R, Nagahara A and Watanabe S designed the study; Murata A collected and analyzed the data; Murata A and Genda T wrote the paper; all authors have read and approved the final version to be published.
Supported by Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Juntendo University Shizuoka Hospital.
Informed consent statement: Written informed consent was obtained from all the patients enrolled in the study.
Conflict-of-interest statement: The authors declare no conflict of interest related to this study.
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: Takuya Genda, MD, PhD, Associate Professor, Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni-shi, Shizuoka 410-2295, Japan. genda@rice.ocn.ne.jp
Telephone: +81-55-9483111 Fax: +81-55-9485088
Received: May 21, 2016
Peer-review started: May 23, 2016
First decision: June 20, 2016
Revised: July 4, 2016
Accepted: August 1, 2016
Article in press: August 1, 2016
Published online: September 7, 2016
Processing time: 106 Days and 1.1 Hours
Abstract
AIM

To clarify the association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and hepatocarcinogenesis after hepatitis C virus eradication.

METHODS

In this study, we enrolled 303 chronic hepatitis C patients who had achieved sustained virological response (SVR) through interferon-based antiviral therapy. Pretreatment AKR1B10 expression in the liver was immunohistochemically assessed and quantified as a percentage of positive staining area by using image-analysis software. A multivariate Cox analysis was used to estimate the hazard ratios (HRs) of AKR1B10 expression for hepatocellular carcinoma (HCC) development after achieving SVR. The cumulative incidences of HCC development were evaluated using Kaplan-Meier analysis and the log-rank test.

RESULTS

Of the 303 chronic hepatitis C patients, 153 (50.5%) showed scarce hepatic AKR1B10 expression, quantified as 0%, which was similar to the expression in control normal liver tissues. However, the remaining 150 patients (49.5%) exhibited various degrees of AKR1B10 expression in the liver, with a maximal AKR1B10 expression of 73%. During the median follow-up time of 3.6 years (range 1.0-10.0 years), 8/303 patients developed HCC. Multivariate analysis revealed that only high AKR1B10 expression (≥ 8%) was an independent risk factor for HCC development (HR = 15.4, 95%CI: 1.8-132.5, P = 0.012). The 5-year cumulative incidences of HCC development were 13.7% and 0.5% in patients with high and low AKR1B10 expression, respectively (P < 0.001). During the follow-up period after viral eradication, patients expressing high levels of AKR1B10 expressed markedly higher levels of alanine aminotransferase and α-fetoprotein than did patients exhibiting low AKR1B10 expression.

CONCLUSION

Chronic hepatitis C patients expressing high levels of hepatic AKR1B10 had an increased risk of HCC development even after SVR.

Keywords: Human AKR1B10 protein; Hepatocellular carcinoma; Chronic hepatitis C; Immunohistochemistry; Risk factor; Sustained virological response

Core tip: Expression of a cancer-related oxidoreductase, aldo-keto reductase family 1 member B10 (AKR1B10) was upregulated in the liver in patients with chronic hepatitis C (CHC). High AKR1B10 expression was associated in a statistically significant manner with the risk of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) was achieved through interferon-based antiviral therapy. Pretreatment AKR1B10 expression of 8% was associated with a > 15-fold-increased risk of HCC development. Thus, AKR1B10 is not only a cancer biomarker but also a novel predictive marker for assessing the risk of HCC development in CHC patients who achieved SVR.