IL-25 Promotes Tumor Progression by Activating the AKT/mTOR Signaling Pathway in Bladder Cancer

Abstract

Background: Bladder cancer is a common tumor of the urinary system. Interleukin-25 is highly expressed in a variety of tumors and leads to poor prognosis. However, the expression and biological role of interleukin-25 in bladder cancer remain unclear. Methods: This study analyzed the differential expression of interleukin-25 (IL-25) and its receptor, interleukin-17 receptor B (IL-17RB), in tumor and adjacent tissues from bladder cancer patients by bioinformatics databases and immunohistochemistry. The impact of IL-25 on bladder cancer cell proliferation and migration was assessed in vitro. Moreover, we used wild-type and IL-25 knockout mice implanted with bladder cancer cells to investigate tumor growth in vivo. Gene set enrichment analysis (GSEA) was employed to elucidate the underlying mechanisms. We further explored the function of interleukin-25 in bladder cancer by cell viability assay and western blot. Angiogenesis was also compared between the wild-type and IL-25 knockout mice. Results: Immunohistochemistry indicated a significantly higher expression of IL-25 in bladder cancer tissues, which correlated with several prognostic markers. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IL-17RB was highly expressed in bladder cancer, and may be related to overall survival of patients. In vitro, IL-25 enhanced the proliferation and migration of bladder cancer cells. IL-25 knockout markedly reduced tumor growth in a murine subcutaneous bladder cancer model. Mechanistic investigations revealed that IL-25 enhanced bladder cancer cell proliferation by activating the AKT (protein kinase B), mammalian target of rapamycin (mTOR) signaling pathway (AKT/mTOR signaling pathway). Additionally, angiogenesis was suppressed in IL-25 knockout mice bearing bladder tumors. Conclusion: Our findings suggest that IL-25 promotes bladder cancer cell proliferation by activating the AKT/mTOR signaling pathway and IL-25 knockout inhibits angiogenesis in bladder cancer. These findings suggest that IL-25 is a potential prognostic marker and therapeutic target in bladder cancer management.