PRSS1 promotes gastric cancer invasion and metastasis by induction of the epithelial-mesenchymal transition and activation of the MAPK/ERK pathway

Background: Protease serine 1 (PRSS1) has been implicated in various pathological processes. This study utilized bioinformatics analyses to evaluate PRSS1 expression in gastric cancer (GC) and explore its role in tumor invasion and metastasis.

Methods: GC-related differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets. A combination of bioinformatics analysis and literature review identified PRSS1 as a hub gene, and its putative functions were inferred by functional enrichment analyses. PRSS1 expression levels were verified in GC tissues, cell lines, and serum samples from patients with metastatic lesions using Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays (ELISAs), and their association with clinicopathological characteristics was analyzed. A stable PRSS1-knockdown cell line was generated to evaluate the effects of the gene on cell migration and invasion, using wound-healing and Transwell migration/invasion assays, as well as in a mouse model of peritoneal metastasis. Altered expression of epithelial-mesenchymal transition (EMT)-related and MAPK/ERK pathway proteins was examined using Western blotting and immunofluorescence.

Results: PRSS1 expression was markedly upregulated in HGC-27 and MKN-45 GC cells relative to that in normal gastric mucosal cells. Serum levels of PRSS1 were significantly elevated in patients with GC, particularly those with advanced-stage disease, and were strongly correlated with unfavorable clinicopathology: vascular invasion, Tumor Node Metastasis (TNM) staging, and lymph node metastasis. Functional enrichment analyses indicated involvement of PRSS1 in multiple biological processes associated with tumor progression. Silencing of PRSS1 suppressed migration and invasion of GC cells in vitro and in vivo peritoneal dissemination. Mechanistically, PRSS1 knockdown reduced the expression of MMP2 and MMP9, increased expression of E-cadherin, reduced that of vimentin, and also modulated MAPK/ERK signaling activity.

Conclusions: These findings indicate that PRSS1 is overexpressed in GC and may contribute to invasion and metastasis, possibly through induction of EMT and activation of MAPK/ERK signaling, highlighting its potential as a therapeutic target.