Abstract
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.
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Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Abbreviations
- IL-22:
-
Interleukin-22
- HCC:
-
Hepatocellular carcinoma
- JAK:
-
Janus kinase
- STAT:
-
Signal transducer and activator of transcription
- AKT:
-
Protein kinase B
- PI3K:
-
Phosphoinositide 3-kinases
- MCL:
-
Myeloid cell leukemia
- BCL:
-
B-cell lymphoma
- MMP:
-
Matrix metalloproteinase
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Funding
This study was funded by the National University of Sciences and Technology, Pakistan (Grant: Students’ Research Funds).
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Authors Fizzah Mansur, Tanzeela Arshad, and Sobia Manzoor contributed equally to the work. All authors read and approved the final manuscript.
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Mansur, F., Arshad, T., Liska, V. et al. Interleukin-22 promotes the proliferation and migration of hepatocellular carcinoma cells via the phosphoinositide 3-kinase (PI3K/AKT) signaling pathway. Mol Biol Rep 50, 5957–5967 (2023). https://doi.org/10.1007/s11033-023-08542-x
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DOI: https://doi.org/10.1007/s11033-023-08542-x