High expression of mesothelin in plasma and tissue is associated with poor prognosis and promotes invasion and metastasis in gastric cancer

Abstract

Mesothelin (MSLN), a tumor-associated antigen, is upregulated in various malignancies, including gastric cancer (GC). In addition, MSLN is found in the blood-stream of affected individuals, where it is referred to as soluble MSLN-related protein (SMRP). This study aims to investigate the role of MSLN in GC and evaluate its potential as a plasma biomarker for diagnosis and prognosis. Toward that end, GC tissues were obtained, upon signed consent, from affected individuals undergoing surgery or endoscopy (n = 82). Quantitative RT-PCR and immunohistochemistry were performed to determine MSLN expression. Simultaneously, The Cancer Genome Atlas (TCGA) database was mined to evaluate global status of MSLN gene expression in gastric cancer. Next, in vitro cell-culture studies were conducted to evaluate MSLN-driven proliferation properties. Using ELISA, sera from 55 GC-affected individuals were tested for MSLN level. Additionally, plasma mesothelin levels were compared in 6 cases before and after surgery. Upregulated MSLN expression was found in GC tissues, compared to adjacent normal tissues (p < 0.001). Cell culture studies with a MSLN-overexpressing stable GC line showed increased cell proliferation and invasion with ectopic MSLN. Additionally, gene-set-enrichment-analysis (GSEA) revealed an association of MSLN with the genes involved in the epithelial-mesenchymal transition and G2/M checkpoint. GC-affected cases showed higher serum MSLN levels, compared to healthy controls, with rapid decrease post-surgery. We found that MSLN upregulation correlates with poor clinical outcome and promotes growth advantage to GC cells in vitro. With further experimental evidences, we propose that MSLN could potentially be used as a plasma biomarker for diagnosis of GC.