PAR-2 promotes invasion and migration of esophageal cancer cells by activating MEK/ERK and PI3K/Akt signaling pathway

Jiexia Sheng; Xu Deng; Qiliang Zhang; Hua Liu; Nannan Wang; Ziquan Liu; Erqing Dai; Quanjun Deng

PAR-2 promotes invasion and migration of esophageal cancer cells by activating MEK/ERK and PI3K/Akt signaling pathway

Int J Clin Exp Pathol. 2019 Mar 1;12(3):787-797. eCollection 2019.

Authors

Jiexia Sheng¹, Xu Deng¹, Qiliang Zhang², Hua Liu³, Nannan Wang¹, Ziquan Liu⁴, Erqing Dai⁵, Quanjun Deng³

Affiliations

¹ Postgraduate Training Basement of Jinzhou Medical University, Chinese People's Armed Police Force Characteristic Medical Center Tianjin City 300162, China.
² Department of Gastroenterology, Tianjin Fourth Central Hospital Tianjin City 300162, China.
³ Department of Gastroenterology, Chinese People's Armed Police Force Characteristic Medical Center Tianjin City 300162, China.
⁴ Department of Disaster Medicine, Tianjin University Tianjin City 300072, China.
⁵ Department of Military Health Care, Chinese People's Armed Police Force Characteristic Medical Center Tianjin City 300162, China.

PMID: 31933886
PMCID: PMC6945182

Abstract

Protease-activated receptor 2 (PAR-2) has been demonstrated to promote invasion and metastasis of certain cancer cells. This study aimed to investigate the mechanism by which PAR-2 regulated invasion and migration of esophageal cancer (EC) cells EC109. A successfully constructed PAR-2 shRNA lentiviral vector (Lenti-PAR-2 shRNA) was stably transfected into EC109 cells, and the expression of PAR-2 in infected cells was detected by quantitative real-time PCR (qRT-PCR) and western blotting. Specific inhibitors, PD98059 (for MEK/ERK) and LY294002 (for PI3K/Akt), were used to confirm the role of MEK/ERK and PI3K/Akt signaling pathways, respectively, in PAR-2-regulated invasion and migration of EC109 cells. A significant decrease in PAR-2 mRNA and protein expression was detected in EC109 cells stably transfected with Lenti-PAR-2 shRNA. The PAR-2 agonist could dramatically promote cell invasion and migration, up-regulate the expression of MMP-9 and TM4SF3, and activate MEK/ERK and PI3K/Akt signaling pathways. However, PAR-2 gene silencing attenuated PAR-2-mediated enhancement of invasion and migration of EC109 cells, significantly down-regulated the mRNA and protein expression of MMP-9 and TM4SF3, and inhibited ERK (Try202/204) and Akt (Ser473) phosphorylation. An effect similar to PAR-2 silencing could be achieved with the two specific MEK/ERK and PI3K/Akt pathway inhibitors. Consequently, these results demonstrated that PAR-2 promoted invasion and migration of esophageal cancer cells EC109 by activating MEK/ERK and PI3K/Akt signaling pathways, which was accompanied by up-regulation of MMP-9 and TM4SF3 expression. Hence, PAR-2 may be a potential candidate for anti-metastasis treatment of EC.

Keywords: MEK/ERK; PI3K/Akt; Protease-activated receptor 2; esophageal cancer; invasion; migration.