Abstract
Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α 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 HIF2α 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 HIF2α 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 HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/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 HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.
Highlights
Liver cancer is one of the most common malignancies and the second leading cause of cancer deaths in men in developing countries [1]
The activation of Hypoxia-inducible factor-2a (HIF2a) led to the enhanced activation of VEGF, cyclin D1, and TGFa/EGFR pathway to mediate Hepatocellular carcinoma (HCC) development and reduce the sensitivity of sorafenib
Our data obtained demonstrate that the COX/ prostaglandin E2 (PGE2) axis acts as a regulator of HIF2a expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFa/EGFR pathway
Summary
Liver cancer is one of the most common malignancies and the second leading cause of cancer deaths in men in developing countries [1]. Hepatocellular carcinoma (HCC) is the most common primary liver cancer [1, 2]. Many patients with HCC lose the opportunity for surgical resection due to late diagnosis [3]. The overall prognosis of patients with HCC remains unsatisfactory. Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation, inhibits angiogenesis, promotes cell apoptosis, and can significantly extend the median survival time of patients with HCC, but only by several months [5]. Many studies have focused on obtaining a better understanding of the mechanisms relevant to HCC development and sorafenib sensitivity with the hope of obtaining new diagnostic, preventive, and therapeutic options
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