COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Purpose: Hypoxia-inducible factor-2 alpha (HIF2 alpha) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2 alpha activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2 alpha 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 HIF2 alpha on hypoxicHCCcells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2 alpha level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2 alpha and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2 alpha activity by promoting HIF2 alpha nuclear translocation via MAPK pathway. The activation of HIF2 alpha then led to the enhanced activation of VEGF, cyclin D1, and TGF alpha/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2 alpha expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGF alpha/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. (C) 2018 AACR.