The Pro‐Migratory and Pro‐Invasive Roles of Cancer‐Associated Fibroblasts Secreted IL‐17A in Prostate Cancer

ABSTRACT Cancer‐associated fibroblasts (CAFs) are key stroma cells that play dominant roles in the migration and invasion of several types of cancer through the secretion of inflammatory cytokine IL‐17A. This study aims to identify the potential role and regulatory mechanism of CAFs‐secreted IL‐17A in the migration and invasion of prostate cancer (PC). CAFs and normal fibroblasts (NFs) were obtained from fresh PC and its adjacent normal tissues, respectively. PC cells LNCaP and DU145 were co‐cultured with the conditioned medium from the CAFs and NFs. IL‐17A level was determined by ELISA in the cell supernatant. CCK‐8, wound healing, Transwell assay, western blot analysis, staining, and primary PC lung metastasis assays were employed in vivo or in vitro to explore the effect of CAFs and IL‐17A secreted by them on proliferation, migration, invasion, epithelial−mesenchymal transition (EMT) and metastasis of PC. CAFs stimulated the migration and invasion of PC cells. Importantly, CAFs exerted their roles by directly secreting IL‐17A, leading to a significant increase in migration and invasion in PC cells. Mechanically, IL‐17A promoted Smad3/p38 MAPK pathway‐mediated EMT process, contributing to cell migration and invasion. Furthermore, CAFs secreting IL‐17A activated the Smad3/p38 MAPK pathway and thus facilitated tumor growth and metastasis in nude mice. This study identifies a novel signaling pathway by which CAFs mediate migration and invasion of PC via upregulation of Smad3/p38 MAPK‐mediated EMT in an IL‐17A‐dependent manner.