PRSS3/mesotrypsin from scirrhous gastric cancer cells and stanniocalcin-1 from cancer-associated fibroblasts mutually promote invasion activity

Scirrhous gastric cancer (SGC) is characterized by rapid cancer-cell infiltration with extensive stromal fibrosis and has a poor prognosis compared to the other types of gastric cancer (GC). SGC cells and cancer-associated fibroblasts (CAFs) might interact with each other in the tumor microenvironment and contribute to progressive invasion. We investigated these cells’ interaction with functional CAFs markers in SGC. Four pairs of CAFs and normal fibroblasts (NFs) and three GC cell lines were used. We examined the CAF marker by RNA sequencing and evaluated the effects of CAFs on SGC cells by invasion assay and morphologic analysis. In silico analysis indicated that stanniocalcin-1 (STC-1) was a CAF marker. The STC-1 mRNA expression in CAFs was significantly higher than in NFs, and was significantly upregulated by the supernatant of an SGC cell line (OCUM-12 cells). STC-1 from CAFs was associated with invasion activity and epithelial-mesenchymal transition of SGC cells. Mesotrypsin (encoded by PRSS3 ) from OCUM-12 cells activated protease-activated receptor 2 (PAR-2) and upregulated STC-1 expression in CAFs via signal transducer and activator of transcription 3 (STAT-3) pathway. In turn, PRSS3 /mesotrypsin was upregulated by STC-1. High mesotrypsin expression contributed to significantly poorer survival in GC patients. PRSS3 /mesotrypsin from SGC cells and the PAR-2/STAT-3/STC-1 axis in CAFs might contribute to the mutual interaction between SGC cells and CAFs that promotes SGC invasion.