Interleukin-17 receptor A drives cancer stem-like properties in colorectal cancer through STAT3 activation.

Cancer stem cells (CSCs) play pivotal roles in tumor relapse, metastasis, and therapy resistance. Interleukin 17 receptor A (IL-17RA) is a key mediator in colorectal cancer (CRC) pathogenesis and progression. Our recent study demonstrated that reduced IL-17RA expression correlates with favorable prognosis in CRC patients and suppresses tumor growth in murine models. This study aimed to investigate the role of IL-17RA in promoting cancer stem-like properties and its impact on colorectal cancer prognosis and chemoresistance. Expression levels of IL-17RA and CSC markers in CRC cells were evaluated using quantitative real-time polymerase chain reaction and Western blotting. Kaplan-Meier analysis of 68 CRC patients revealed that high IL-17RA expression is associated with poor clinical outcomes. To investigate IL-17RA's functional role, CRC cells with stable IL-17RA overexpression were analyzed for changes in CSC marker expression, sphere formation, and 5-fluorouracil (5-FU) resistance. IL-17RA overexpression significantly increased CSC marker expression, including cluster of differentiation 133 (CD133), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), sex determining region Y-box 2 (SOX2), and enhanced tumor sphere formation and 5-FU resistance in SW620 cells. Specific inhibitors of IL-17RA signaling, such as the STAT3 inhibitor Stattic, reduced the expression of CD133, LGR5, ALDHA1, SOX2 and c-MYC, as well as tumor sphere formation in SW620 cells. These findings elucidate a novel IL-17RA-STAT3 axis that regulates CSC properties in CRC and highlight IL-17RA as a promising prognostic biomarker and therapeutic target for CRC treatment.