Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1120
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
To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis.
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.
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.
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.
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.