Liver is known for its remarkable capacity to regenerate following surgical resection or in response to drug-induced liver injury. The regenerative capacity of the liver is of immense importance as it affects outcomes of liver toxicity, post-transplant survival and cancer pathogenesis. It is know that following surgical resection of up to 70% liver (partial hepatectomy or PHX), the remnant liver regrows back precisely to the pre-PHX size. Interestingly, many of the pathways involved in normal liver regeneration are oncogenic signaling pathways also involved in cancer pathogenesis. However, these pathways are turned off at precise times during normal liver regeneration, whereas they remain constantly active in cancers. These observations support the existence of specific mechanisms that terminate liver regeneration in a timely fashion and regulate liver size growth following PHX. We are testing the hypothesis that signaling pathways that terminate liver regeneration following PHX are dysfunctional during pathogenesis of hepatocellular carcinoma (HCC), the most common hepatic malignancy. To this end, we are investigating the role of nuclear receptor Hepatocyte Nuclear Factor-4α (HNF4α) in inhibition of hepatocyte proliferation and prevention of HCC pathogenesis.
HCC is the most common hepatic malignancy with extremely grim prognosis and limited treatment options. Incidence of HCC is rising in the US and the world. However, the mechanisms of HCC pathogenesis are not completely known. We are investigating the role of bile acids in HCC pathogenesis. Bile acids are amphipathic molecules produced in the liver and are involved in digestion and absorption of fats and vitamins. Increase in bile acid levels results in hepatic inflammation, cholestatic liver diseases and liver cancer. Higher bile acids are known to promote cancer development in the colon and the liver but the mechanisms are not known. We are investigating the signaling crosstalk between Wnt/ β -catenin pathway and bile acids during HCC pathogenesis.
Recent studies have shown that Hippo Kinase signaling pathway is involved in organ size regulation of the liver and deregulation of this pathway results in HCC development. The downstream effector of this pathway is a protein called yes-associated protein (Yap). Yap is a transcriptional coactivator and is known to stimulate pro-mitogenic signaling. However, recent studies in our laboratory have shown that Yap may also be involved in hepatic differentiation. We are investigating the role of Yap and Hippo Kinase signaling pathway in postnatal hepatic differentiation.