Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

Abstract

AbstractBackgroundInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL‐17 binds to interleukin‐17 receptor A (IL‐17RA); however, the role of IL‐17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL‐17RA in human CRC tissues and the progression of CRC in humans and mice.MethodsThe expressions of IL‐17RA and epithelial‐mesenchymal transition (EMT)‐related genes were examined in CRC cells and tissue samples by quantitative real‐time polymerase chain reaction. The role of IL‐17RA in pathogenesis and prognosis was evaluated using a Chi‐squared test, Kaplan–Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor‐bearing mice model was executed to evaluate the role of IL‐17RA in tumor growth, vascularity and population of infiltrating immune cells.ResultsIL‐17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL‐17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL‐17RA expression exhibited significantly worse overall and CRC‐specific survival than those with low IL‐17RA expression. Functional assessment suggested that the knockdown of IL‐17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT‐related gene expression. In a tumor‐bearing mouse model, decreased IL‐17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs).ConclusionReduced IL‐17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL‐17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL‐17RA expression was identified to be independently associated with the prognosis of patients with CRC.