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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2016; 22(33): 7486-7499
Published online Sep 7, 2016. doi: 10.3748/wjg.v22.i33.7486
Aberrant regulation of Wnt signaling in hepatocellular carcinoma
Li-Juan Liu, Shui-Xiang Xie, Ya-Tang Chen, Jing-Ling Xue, Chuan-Jie Zhang, Fan Zhu
Li-Juan Liu, Ya-Tang Chen, Fan Zhu, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
Shui-Xiang Xie, Department of Pathogenic Biology, Gannan Medical University, Gannan 341000, Jiangxi Province, China
Jing-Ling Xue, Department of Pathology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
Chuan-Jie Zhang, Department of Children Health Care, Wuhan Medical Care Center for Women and Children, Wuhan 430016, Hubei Province, China
Fan Zhu, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan 430071, Hubei Province, China
Author contributions: Liu LJ and Xie SX equally contributed to this paper with literature review and editing; Chen YT participated in drawing the graphs of the signaling pathways; Xue JL prepared a draft of the “canonical Wnt signaling” portion; Zhang CJ drafted the “non-canonical Wnt signaling” portion; Zhu F was responsible for the design, editing and revision of the article, and approval of the final version.
Supported by National Natural Science Foundation of China, No. 31470264 and No. 81502418; the Key Program of Natural Science Foundation of Hubei Province of China, No. 2014CFA078; the Hubei Provincial Natural Science Foundation of China, No. 2015CFB168 and No. 2012FFB04304; the Scientific Research Innovation Team in Hubei, No. 2015CFA009; the General Financial Grant from the China Postdoctoral Science Foundation, No. 2014M550411; the Fundamental Research Funds for the Central Universities, No. 2042014kf0029; the Tianqing Liver Disease Research Fund of the China Foundation for Hepatitis Prevention and Control, No. TQGB20140250; the Innovation Seed Fund of Wuhan University School of Medicine; the Science and Technology Department Supported Program of Jiangxi Province of China, No. 2010BSA13500; the Science and Technology Project of Education Department of Jiangxi Province of China, No. GJJ11570.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
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: Fan Zhu, PhD, Professor, Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan 430071, Hubei Province, China. fanzhu@whu.edu.cn
Telephone: +86-27-68759906 Fax: +86-27-68759906
Received: March 27, 2016
Peer-review started: March 28, 2016
First decision: May 12, 2016
Revised: June 7, 2016
Accepted: July 20, 2016
Article in press: July 20, 2016
Published online: September 7, 2016
Processing time: 160 Days and 19 Hours
Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as “canonical”) and CTNNB1-independent (often referred to as “non-canonical”) pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.

Keywords: Hepatocellular carcinoma; Wingless/int-1; Catenin β1; Crosstalk; Canonical wingless/int-1 signaling; Non-canonical wingless/int-1 signaling

Core tip: The development of hepatocellular carcinoma (HCC) is regarded as a multistage process in which multiple genetic alterations are necessary. The wingless/int-1 (Wnt) pathway is a signaling mechanism that is frequently activated in HCC, especially the canonical Wnt pathway. Moreover, two main non-canonical pathways are also involved in the regulation of hepatocarcinogenesis. Interestingly, the non-canonical Wnt pathway could antagonize the canonical Wnt pathway in HCC. Crosstalk between other signaling pathways and the Wnt pathway has also been shown to promote tumorigenesis. This review highlights the details regarding the Wnt pathway in HCC, which might provide new potential targets for HCC prevention and therapy.