The role of NRF2 on VEGFA/VEGFR expression, hepatic vascularization and cancer growth

The transcriptional enhancer protein Nuclear factor (erythroid-derived 2)-like 2 (NRF2) stimulates expression of a wide range of genes in response to oxidative and electrophilic stress via binding to the DNA element known as the antioxidant response element (ARE) to maintain organismal homeostasis. While previous research initially identified the importance of NRF2 in drug detoxication, further research has revealed transactivation of genes that function more broadly, including those that influence energy metabolism and tissue regeneration. The goals of this project were to characterize how NRF2 signaling influences the liver microenvironment to affect cancer progression as well as shape the development of the liver vasculature by utilizing genetic mouse models elevated and deficient in NRF2 signaling. Experiments have revealed NRF2 affects transactivation of vascular endothelial growth factor A (VEGFA) directly, through a putative antioxidant response element (ARE) located in the promoter region. To determine how NRF2 could influence the liver microenvironment through alterations VEGFA signaling between hepatocytes and liver sinusoidal endothelial cells, VEGFA and VEGFA receptors were examined in primary isolated cultures. Our studies identified elevated protein levels of VEGFA and reduced protein levels of vascular endothelial growth factor receptor 2 (VEGFR-2) in hepatocytes and liver sinusoidal endothelial cells with both elevated and deficient NRF2 signaling, respectively. Further investigation revealed that increased transcription of hepatocyte growth factor (HGF) was found to coincide with the reduction of VEGFR-2 seen with elevated and deficient NRF2 signaling and that elevated NRF2 signaling also reduced the level of circulating VEGFR-2 protein. The NRF2-dependent alterations to the liver microenvironment were found to enhance cancer progression in mice with elevated and deficient NRF2 signaling. To research if alterations of liver vasculature development were present in NRF2-deficient mice, the hepatic portal vasculature was probed with resin casting. Vascular corrosion casting and Micro-computed tomography (mu-CT) revealed that ductus venosus closure was abolished in many mice. In total, imbalanced NRF2 signaling can enhance cancer progression and alter normal liver development.