COX-2/PGE2 Axis Regulates HIF-2{alpha} Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Purpose: Hypoxia-inducible factor (HIF)-2α is regarded as a preferential target for individualized HCC treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF-2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF-2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration and invasion abilities were measured to analyze the effects of HIF-2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF-2α level and activity, which then reduce the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF-2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF-2α activity by promoting HIF-2α nuclear translocation via MAPK pathway. The activation of HIF-2α then led to the enhanced activation of VEGF, cyclin D1, and TGF-α/EGFR pathway to mediate HCC progression and reduce the sensitivity of sorafenib. More importantly, COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF-2α expression and activity to promote HCC progression and attenuate sorafenib sensitivity by constitutively activating the TGF-α/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.

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