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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2016; 22(45): 9921-9932
Published online Dec 7, 2016. doi: 10.3748/wjg.v22.i45.9921
Understanding the role of PIN1 in hepatocellular carcinoma
Chi-Wai Cheng, Ka-Wai Leong, Eric Tse
Chi-Wai Cheng, Ka-Wai Leong, Eric Tse, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
Author contributions: Cheng CW, Leong KW and Tse E conceived, wrote and approved the manuscript.
Conflict-of-interest statement: All authors declare no conflict of interest related to this publication.
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: Eric Tse, MBBS, PhD, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. ewctse@hku.hk
Telephone: +86-852-22553975 Fax: +86-852-28726896
Received: August 23, 2016
Peer-review started: August 24, 2016
First decision: September 12, 2016
Revised: September 26, 2016
Accepted: October 30, 2016
Article in press: October 30, 2016
Published online: December 7, 2016
Processing time: 105 Days and 4.4 Hours
Abstract

PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, β-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in β-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.

Keywords: Phosphorylation; Hepatocellular carcinoma; PIN1; Isomerization; Hepatocarcinogenesis

Core tip: PIN1 specifically binds and catalyses isomerization of the pSer/Thr-Pro motif of target proteins, thereby modulating their functions. Many PIN1-interacting proteins are involved in cellular transformation and maintenance of malignant phenotype, and overexpression of PIN1 is frequently found in various cancer types, including hepatocellular carcinoma (HCC). Through interacting with regulatory proteins of key signalling pathways, such as β-catenin, cyclin D1, and HBx, PIN1 drives and amplifies the oncogenic signals essential for the development of HCC. Given its diverse oncogenic functions in hepatocarcinogenesis, PIN1 represents a potential therapeutic target in the treatment of HCC.