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

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.

Lentiviral vector mediated expression of Bax and hepatocyte growth factor inhibits vein graft thickening in a rabbit vein graft model.

Vein graft failure caused by vein graft thickening of the arterialized vein after bypass surgery is a main problem in clinical vascular surgery. Gene therapy is increasingly being recognized as a relevant treatment option for vein graft failure. In this study, we aimed to develop a novel recombinant lentivirus for the delivery of hepatocyte growth factor (HGF) and Bax in a rabbit vein graft model of bypass grafting. A bypass model was made in rabbits using the right jugular vein interposed end-to-end to the ipsilateral carotid artery. A lentivirus vector harboring HGF and Bax cDNAs (Lenti-HGF-Bax) was constructed and transduced into the venous grafts. Vein grafts were stained with hematoxilyn and eosin, and Masson. HGF and Bax expression in vein grafts was detected by immunohistochemical and Western blot analysis. Our results showed that vein graft thickening was reduced by 47.2 ± 7.4% in lenti-HGF-Bax treated rabbits, compared to controls. Meanwhile, the ratio of intima/media area was reduced in lentil-HGF-Bax treated rabbits, compared to controls. The number of HGF and Bax positive cells was increased in vein grafts from rabbits treated by lenti-HGF-Bax, compared to those from controls. Furthermore, protein levels of HGF and Bax were both significantly increased in grafts derived from rabbits treated by lenti-HGF-Bax, compared to those from control. In conclusion, Lenti-HGF-Bax inhibits vein graft thickening in vein grafts and is a promising agent for preventing vein graft failure.