70P - Increased expression of interleukin-17 receptor A (IL-17RA) promotes cancer stem-like properties, resistance to 5-fluorouracil, and the expression of ATP-binding cassette transporters in colorectal cancer cells

Background

Colorectal cancer stem cells play crucial roles in tumor relapse, metastasis, and therapy failure. 5-Fluorouracil (5-FU) is commonly prescribed for colorectal cancer (CRC) patients, but resistance to 5-FU is a major cause of treatment failure. Interleukin-17 (IL-17) is a proinflammatory cytokine that promotes tumorigenesis in various cancers, including CRC. Current evidence suggests that IL-17 binds to the interleukin-17 receptor A (IL-17RA). Our recent publication revealed that high IL-17RA expression in tumor tissues is associated with poor prognosis in CRC patients.

Methods

We evaluated the role of IL-17RA in pathogenesis and prognosis using Chi-square tests and Kaplan-Meier analysis in 234 CRC patients. Two IL-17RA stable overexpression CRC cell lines, SW480 and SW620, were established to examine the expression of stemness-like and ATP-binding cassette (ABC) transporter genes by quantitative real-time RT-PCR and Western blotting. Sphere formation and 5-FU resistance were assessed using tumor sphere formation assays and in vitro cytotoxicity assays, respectively.

Results

Patients with high IL-17RA expression had significantly worse overall, disease-free, and disease-specific survival. Stem cell markers CD133, LGR5, ALDH1A1, and stemness genes SOX2 and c-MYC were significantly increased in IL-17RA-overexpressing SW620 cells compared to control cells. Similarly, CD133, LGR5, ALDH1, and SOX2 were upregulated in IL-17RA stable overexpressing SW480 cells. Furthermore, IL-17RA overexpression enhanced sphere formation, self-renewal, and 5-FU resistance. ABC transporters ABCB7, ABCD1, and ABCB1 were overexpressed in IL-17RA-overexpressing cells compared to control cells.

Conclusions

IL-17RA enhances the expression of stemness-like genes and some ABC transporters, as well as self-renewal and 5-FU resistance. Therefore, IL-17RA could serve as a potential prognostic biomarker and a promising therapeutic target in CRC.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

The Ministry of Science and Technology, Taiwan.

Disclosure

All authors have declared no conflicts of interest.