Interleukin-22 promotes cancer stemness and chemotherapy resistance in colorectal cancer via epidermal growth factor receptor/extracellular signal-regulated kinase pathway

Background: Interleukin-22 (IL-22) belongs to the IL-10 cytokine family, recognized for its ability to modulate diverse immune responses. Previous studies have indicated that IL-22 promotes Cancer advancement and metastasis. However, the precise function of IL-22 in colorectal Cancer (CRC) remains unclear.

Aim: To investigate the role of IL-22 in promoting stem cell-like characteristics and chemotherapy resistance in CRC cells, as well as to elucidate the mechanisms underlying these effects.

Methods: HCT116 cells were treated with IL-22 (50 ng/mL) and oxaliplatin (L-OHP, 5 μg/mL). A series of functional assays - including cell counting kit-8 assay, tumor sphere formation assay, and cell Apoptosis assay - were conducted to assess the effects of IL-22 on cell viability and stem cell-like characteristics. The expression of stemness-related markers (SOX2, Oct4, NANOG, and Bmi-1) was examined using Western blot analysis. Additionally, the total and phosphorylated levels of epidermal growth factor receptor (EGFR), protein kinase B (Akt), and extracellular signal-regulated kinase (ERK) were evaluated by Western blot. An EGFR Inhibitor, osimertinib (Osi), was used to assess the pathway's functional relevance.

Results: IL-22 treatment promotes CRC cell proliferation, enhances sphere formation, and elevates the expression of stem cell markers, including SOX2, Oct4, NANOG, and Bmi-1. IL-22 treatment increases the phosphorylation of EGFR, Akt, and ERK. Additionally, IL-22 treatment mitigates the cytotoxic effects and the ability to induce Apoptosis of L-OHP. Furthermore, IL-22 treatment activated the EGFR/ERK signaling pathway by increasing the phosphorylation of EGFR, Akt, and ERK. Importantly, the use of the EGFR Inhibitor Osi significantly counteracted the chemoresistance induced by IL-22 in CRC cells.

Conclusion: IL-22 promotes tumor growth and induces chemotherapy resistance in CRC cells by activating the EGFR/ERK signaling pathway. These findings suggest that targeting IL-22 or its downstream signaling may offer novel therapeutic strategies in CRC.

Colorectal cancer; Epidermal growth factor receptor; Extracellular signal-regulated kinase; Interleukin-22; Oxaliplatin.