Wnt/-catenin signaling is pertinent in liver biology in regulating zonation, regeneration, development and metabolism. However aberrations in this pathway have been reported in hepatic fibrosis, hepatic injury, hepatoblastomas and hepatocellular cancer (HCC). Targeting -catenin in HCC is imminent. It is the 3rd fatal cancer worldwide and its incidence and associated death rates have steadily increased since the 1980s. Cellular & molecular basis of HCC is poorly understood. Wnt signaling has been deemed active in 17-40% of HCCs due to various reasons and around 20-40% of all HCCs harbor monoallelic somatic mutations in the exon-3 of the -catenin gene (CTNNB1) that encodes for a non-serine/threonine phosphorylatable, stable and constitutively active protein, making it an attractive therapeutic target. We have made several important and some paradoxical observations over the last few years including identification of novel interactions and cross-regulations between -catenin and other molecules. These may have significant biological and translational implications mandating an in-depth analysis that may have widespread implications in not just HCC but other hepatic pathologies where -catenin targeting may be of essence such as hepatic fibrosis, injury and metabolic syndrome. The overarching hypothesis of the proposal is that therapeutic targeting of -catenin must take into account existing redundancies and crosstalk with specific signaling pathways, which need to be comprehensively elucidated. We will test these hypotheses in three distinct but thematically related aims.
In aim 1, we will investigate the mechanism of oxidative stress dependent enhanced hepatocarcinogenesis in -catenin conditional knockout mice (Hep--Cat KO) to address if enhanced HCC is a murine 'artifact' due to the role of -catenin in vitamin C biosynthesis in murine hepatocytes. We identified a novel role of -catenin signaling in vitamin C biosynthesis in the murine liver, whic is a known major antioxidant. Unlike humans and primates, rodents synthesize vitamin C in the hepatocytes and regular mouse chow is devoid of ascorbic acid. We hypothesize that increased HCC and oxidative stress in Hep--Cat KO is due to compromised vitamin C biosynthesis and its normalization will alleviate HCC and demonstrate -catenin to be a global therapeutic target in HCC.
In aim 2 we will investigate mechanism and biological implications of PDGFR? upregulation and activation after -catenin inhibition in HCC cells. We hypothesize that PDGFR? upregulation along with the activation of its specific downstream signaling arm is an important mechanism that will allow growth of HCC after -catenin inhibition and that understanding the role and regulation of this phenomena will bear significantly on efficacious HCC treatment.
In aim 3, we will investigate the role and regulation of ?-catenin stabilization following inhibition of -catenin expression in the liver. We hypothesize that ?-catenin stabilization during -catenin inhibition in HCC will prevent any untoward effect related to disruption of cell-cell adhesion. All the proposed studies in the grant will utilize a balance of i vitro and in vivo set of experiments and the expected outcomes will be highly relevant and translational.
The research proposal focuses on -catenin-directed personalized medicine in hepatic pathologies with aberrant activation of canonical Wnt signaling. The studies will address mechanisms of resistance to therapies as well as address useful redundancies that may prevent untoward adverse effects due to dual function of -catenin. Role of - catenin in regulating vitamin C synthesis and oxidative stress will be addressed as well.
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