BACKGROUND: Interleukin-22 (IL-22) is a pro-inflammatory cytokine released during the immune response in chronic liver injury. Although IL-22 mediates tissue regeneration, its uncontrolled production may generate a carcinogenic environment resulting in hepatocellular carcinoma (HCC). This study aims to identify the effect of IL-22 on anti-apoptotic and metastatic genes and the molecular pathways responsible for IL-22-mediated hepatic carcinogenesis. METHODS AND RESULTS: Three cancerous liver lines, HepG2, SNU-387, Huh7, and one normal liver line, THLE2, were treated with IL-22. RT-qPCR analysis was conducted to study the role of IL-22 in altering the expression levels of anti-apoptotic genes, MCL-1 and BCL-2, and metastatic genes, MMP-7 and MMP-9. A significant increase in expression levels of these genes was observed after IL-22 treatment. Furthermore, to explore the major pathways involved in IL-22-mediated upregulation of anti-apoptotic and metastatic genes, cells were treated with inhibitors of JAK/STAT and PI3K/AKT pathways along with IL-22. Resultantly, a significant decrease in expression levels of target genes was observed, indicating the involvement of JAK/STAT and PI3K/AKT signaling cascades in IL-22-mediated oncogenesis. Finally, Cell Scratch assay was performed to check the effect of IL-22 and inhibitors of JAK/STAT and PI3K/AKT on the metastatic potential of liver cells. While migration was observed in Huh7 and THLE2 cells treated with IL-22, no migration was observed in cells treated with IL-22 along with JAK/STAT and PI3K/AKT inhibitors. Results indicate that IL-22 encourages metastasis in HCC cells via the JAK/STAT and PI3K/AKT pathways. CONCLUSION: Results showed that IL-22 upregulates anti-apoptotic and metastatic genes in HCC through JAK/STAT and PI3K/AKT signaling pathways.

Department of Surgery Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Laboratory of Cancer Treatment and Tissue Regeneration Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Czechia

Molecular Virology and Immunology Research Group Atta Ur Rahman School of Applied Biosciences National University of Sciences and Technology Islamabad Pakistan

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