Hypoxia-induced HIF1A activates DUSP18-mediated MAPK14 dephosphorylation to promote hepatocellular carcinoma cell migration and invasion

Background: Hepatocellular Carcinoma (HCC) is recognized as the second leading cause of cancer-associated deaths globally. Hypoxia-inducible factor 1alpha (HIF1A) has been documented to promote HCC cell migra-tion, invasion and cell cycle. Dual specificity phosphatase 18 (DUSP18) has been predicted to be up-regulated in hypoxia and its expression is positively linked to HIF1A expression in HCC cells. However, their function and molecular mechanism have not been investigated in HCC in depth. Purpose: This study aimed to uncover the functional roles of HIF1A and DUSP18, as well as relevant mechanisms underlying their regulation in HCC cells. Methods: RT-qPCR and western blot were performed to examine gene expression. Functional assays were implemented to reveal the regulatory impact of target genes on HCC cells. Mechanism experiments were con-ducted to analyze gene interaction. Results: DUSP18 was found to have significantly high expression in hypoxia-induced HCC cells. HIF1A promoted HCC cell migration, invasion and cell cycle by transcriptionally activating DUSP18. DUSP18 mediated MAPK14 dephosphorylation to weaken MAPK14 activity, which further inhibited MAPK14-mediated TP53 phosphoryla-tion, consequently promoting multiple biological behaviors of HCC cells. Conclusion: Hypoxia-induced HIF1A activates DUSP18 transcription to further promote MAPK14 dephosphory-lation, thereby suppressing TP53 phosphorylation and functionally promoting malignant behaviors of HCC cells.