Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1120-1133
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1120
Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma
Liang Sun, Pi-Bao Li, Yan-Fen Yao, Ai-Yuan Xiu, Zhi Peng, Yu-Huan Bai, Yan-Jing Gao
Liang Sun, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Liang Sun, Pi-Bao Li, Yan-Fen Yao, Department of Critical Care Medicine, Shandong Traffic Hospital, Jinan 250000, Shandong Province, China
Ai-Yuan Xiu, Zhi Peng, Yu-Huan Bai, Yan-Jing Gao, Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Sun L and Gao YJ designed the research; Sun L, Xiu AY and Peng Z performed the research; Li PB and Bai YH contributed new reagents or analytic tools; Sun L and Yao YF analyzed the data; Sun L wrote the paper.
Supported by Jinan College Innovation Plan, No. 26010105081333; and Shandong Social Development Plan, No. 26010104011343.
Institutional animal care and use committee statement: The use and care of experimental animals were approved by the Institutional Animal Care and Use Committee, Qilu Hospital of Shandong University.
Conflict-of-interest statement: The authors declare that they have no competing interests.
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: Yan-Jing Gao, PhD, Chief Doctor, Professor, Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, West Wenhua Road, Jinan 250012, Shandong Province, China. gaoyanjing@sdu.edu.cn
Telephone: +86-531-86927544
Received: December 8, 2017
Peer-review started: December 8, 2017
First decision: December 20, 2017
Revised: December 29, 2017
Accepted: January 24, 2018
Article in press: January 24, 2018
Published online: March 14, 2018
Processing time: 95 Days and 2.9 Hours
Abstract
AIM

To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis.

METHODS

PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both in vitro and in vitro. Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers.

RESULTS

The prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage (P = 0.001, chi-square test), larger tumor size (P = 0.032, chi-square test), and high microvascular invasion rate (P = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and HepG2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and HepG2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and HepG2 cells via ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability.

CONCLUSION

These data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.

Keywords: Hepatocellular carcinoma; Proteinase-activated receptor 2; Epithelial-mesenchymal transition

Core tip: The role of proteinase-activated receptor 2 (PAR2) in tumor progression especially metastasis of hepatocellular carcinoma and how it is regulated are still unclear. In this study, we found that PAR2 was upregulated in hepatocellular carcinoma (HCC) tumor tissues and related with poor prognosis in HCC patients. In addition, we proved that PAR2 could not only promote the proliferation and metastasis ability of SMMC-7721 and HepG2 cells in vitro, but also promoted xenograft tumor growth and HCC cell liver metastasis in vivo. These effects were mediated by the activation of ERK, which further induced epithelial-mesenchymal transition of HCC cells.