Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2025; 17(8): 108535
Published online Aug 15, 2025. doi: 10.4251/wjgo.v17.i8.108535
Interleukin-22 promotes cancer stemness and chemotherapy resistance in colorectal cancer via epidermal growth factor receptor/extracellular signal-regulated kinase pathway
Hong-Xun Ruan, Yan-Le Fang, Xiao-Ning Qin, Lin Lin
Hong-Xun Ruan, Yan-Le Fang, Xiao-Ning Qin, Lin Lin, The Third Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, Hebei Province, China
Author contributions: Lin L designed and coordinated the study; Ruan HX acquired and analyzed data; Fang YL performed the experiments; Qin XN and Lin L wrote the manuscript; All authors read and approved the final version of the manuscript.
Institutional review board statement: The article does not involve humans or animals, so it does not require approval from an institutional review board.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated and/or analyzed in the experiment are available from the corresponding author on reasonable request at linlin779242000@163.com.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lin Lin, MD, The Third Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050004, Hebei Province, China. linlin779242000@163.com
Received: April 17, 2025
Revised: May 26, 2025
Accepted: July 11, 2025
Published online: August 15, 2025
Processing time: 119 Days and 16.3 Hours
Abstract
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.

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

Core Tip: This study reveals that interleukin-22 (IL-22) enhances stem cell-like traits and promotes resistance to oxaliplatin in colorectal cancer (CRC) cells. Mechanistically, IL-22 activates the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase signaling pathway. Inhibition of EGFR with osimertinib reverses IL-22-induced chemoresistance. These findings highlight IL-22 as a critical mediator of therapeutic resistance and a potential target for overcoming drug resistance in CRC treatment.