Department of Pharmacology, Toxicology and Therapeutics
Ph.D., University of Louisiana at Monroe, 2003
Postdoctoral, Texas A&M University, 2003-2004
Postdoctoral, University of Pittsburgh, 2004-2008
Pathogenesis of Hepatocellular Carcinoma (HCC), Regulation of Hepatocyte Proliferation during Liver Regeneration
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 known that following surgical resection of up to 70% of the 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 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-4a (HNF4a) 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/b-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.
Walesky C, Gunewardena S, Terwilliger EF, Edwards G, Borude P, Apte U. Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol. 2013 Jan;304(1):G26-37.
Hays A, Apte U, Hagenbuch B. Organic Anion Transporting Polypeptides Expressed in Pancreatic Cancer May Serve As Potential Diagnostic Markers and Therapeutic Targets for Early Stage Adenocarcinomas. Pharm Res. 2013 Jan 11.
Weaver BP, Zhang Y, Hiscox S, Guo GL, Apte U, Taylor KM, Sheline CT, Wang L, Andrews GK. Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PLoS One. 2010 Oct 4;5(10): e13158.
Behari J, Yeh TH, Krauland L, Otruba W, Cieply B, Hauth B, Apte U, Wu T, Evans R, Monga SP. Liver-specific beta-catenin knockout mice exhibit defective bile acid and cholesterol homeostasis and increased susceptibility to diet-induced steatohepatitis. Am J Pathol. 2010 Feb;176(2):744-53.
Apte U, Singh S, Zeng G, Cieply B, Virji MA, Wu T, Monga SP. Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury. Am J Pathol. 2009 Sep;175(3):1056-65.
Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donthamsetty S, Orr A, Monga SP, Wu C, Michalopoulos GK. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology. 2009 Sep;50(3):844-51.
Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SP. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology. 2008 Jan;47(1):288-95.
Apte U, Zeng G, Thompson MD, Muller P, Micsenyi A, Cieply B, Kaestner KH, Monga SP. beta-Catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1578-85.
Zeng G, Apte U, Cieply B, Singh S, Monga SP. siRNA-mediated beta-catenin knockdown in human hepatoma cells results in decreased growth and survival. Neoplasia. 2007 Nov;9(11):951-9.
Apte U, Zeng G, Muller P, Tan X, Micsenyi A, Cieply B, Dai C, Liu Y, Kaestner KH, Monga SP. Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice. Hepatology. 2006 Oct;44(4):992-1002.
Udayan Apte, Ph.D.