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 migration, 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 conducted 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 phosphorylation, consequently promoting multiple biological behaviors of HCC cells.

Conclusion: Hypoxia-induced HIF1A activates DUSP18 transcription to further promote MAPK14 dephosphorylation, thereby suppressing TP53 phosphorylation and functionally promoting malignant behaviors of HCC cells.