Activation of the IL-17 signalling pathway by the CXCL17-GPR35 axis affects drug resistance and colorectal cancer tumorigenesis

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and drug resistance following prolonged treatment leads to downregulation of the efficacy of chemotherapy against CRC. CXCL17 is an inflammatory factor that plays a crucial role in tumorigenesis. However, the function of the CXCL17-GPR35 axis in CRC and resistance to chemotherapy is not entirely clear. Bioinformatic analysis was used to identify differentially expressed genes (DEGs) in oxaliplatin (OXA)-resistant CRC tumour tissues compared to OXA-sensitive counterparts. To further determine the function of CXCL17 in taxol-resistant CRC cells (HCT15), proliferation, migration, invasion, cell cycle, and apoptosis were analysed by CCK-8, wound healing, Transwell (R), and flow cytometry assays, respectively. In addition, RNA sequencing, western blotting, CCK-8, wound healing, and Transwell (R) assays were used to further identify and confirm the downstream effects of CXCL17 regulation on taxol resistance. Our study found that CXCL17 and GPR35 were upregulated in OXA-resistant tumour tissues compared to in OXA-sensitive tissues. CXCL17 silencing significantly decreased the viability, migration, and invasion of taxol-resistant CRC cells. CXCL17 silencing arrested taxol-resistant CRC cells in the G2/M phase and promoted apoptosis. The IL-17 signalling pathway is involved in regulation of the CXCL17-GPR35 biological axis in HCT15 cells, and the addition of IL-17A distinctly reversed the decreased proliferation, migration, and the enhanced apoptosis of HCT15 cells upon CXCL17 deletion. In summary, these findings demonstrate that the CXCL17-GPR35 axis and IL-17 signalling pathway are involved in mediating CRC tumorigenesis and drug-resistance. Inhibition of the CXCL17-GPR35 axis and IL-17 may hence be promising therapeutic targets for CRC resistance to OXA.

Automated summary

Colorectal cancer (CRC) is a commonly diagnosed cancer, but resistance to chemotherapy reduces its effectiveness. CXCL17 is an inflammatory factor that plays a crucial role in tumorigenesis. However, the function of the CXCL17-GPR35 axis in CRC and drug resistance is not fully understood.