Interleukin-22 Promotes Lung Adenocarcinoma (LUAD) Progression Through Activation of the PI3K/AKT Signaling Pathway.

INTRODUCTION Lung Adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, with a limited understanding of cytokine-mediated molecular mechanisms driving its progression. Interleukin-22 (IL-22), a cytokine involved in inflammation and tissue regeneration, has been implicated in several malignancies, but its role in LUAD is unclear. This study aimed to investigate IL-22 expression, regulation, and its functional impact on LUAD progression via the PI3K/AKT signaling pathway.

METHODS IL-22 expression was analyzed in six LUAD and four normal bronchial epithelial cell lines using RT-qPCR and ELISA. Validation across TCGA and GSCA datasets assessed transcriptional levels, promoter methylation, and pathway enrichment. Functional assays, including CCK-8, colony formation, Transwell invasion, and wound-healing assays, were performed with recombinant IL-22 (0-100 ng/mL) in A549 and H1299 cells, with or without the PI3K inhibitor LY294002. Western blot analysis determined pathway activation, and luciferase assays verified miRNA regulation of IL-22.

RESULTS IL-22 was significantly upregulated in LUAD at both mRNA and protein levels, correlated with promoter hypomethylation, and was associated with poor prognosis. Functional studies demonstrated that IL-22 enhanced proliferation, clonogenicity, invasion, and migration in a dose-dependent manner via PI3K/AKT phosphorylation. LY294002 co-treatment reversed these effects. Moreover, hsa-miR-21-5p directly targeted IL-22 3'UTR and was significantly downregulated in LUAD, indicating a regulatory role in IL-22 overexpression.

DISCUSSION This study identifies IL-22 as a cytokine that promotes malignant phenotypes in LUAD cells through activation of the PI3K/AKT signaling pathway. The integration of functional assays with multi-omics analyses suggests that IL-22 overexpression is driven by promoter hypomethylation and reduced hsa-miR-21-5p-mediated post-transcriptional regulation. While these findings support a mechanistic role for IL-22 in LUAD progression, further in vivo and clinical studies are required to validate the relevance of the IL-22/PI3K/AKT axis within the tumor microenvironment and its translational potential.

CONCLUSION IL-22 promotes LUAD progression by activating the PI3K/AKT signaling pathway and inducing EMT, while its upregulation is modulated by promoter hypomethylation and miR- 21-5p suppression. The IL-22/PI3K/AKT axis represents a potential therapeutic target for LUAD management.