PhD, University of Louisiana at Monroe, 2003
Postdoctoral Fellowship, University of Pittsburgh, 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 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.
Walesky C, Gunewardena S, Terwilliger EF, Edwards G, Borude P, Apte U.Hepatocyte-Specific Deletion of Hepatocyte Nuclear Factor 4 alpha in Adult Mice Results in Increased Hepatocyte Proliferation. Am J Physiol Gastrointest Liver Physiol. 2012 Oct 25. [Epub ahead of print] PMID: 23104559
Borude P, Edwards G, Walesky C, Li F, Ma X, Kong B, Guo GL, Apte U.Hepatocyte specific deletion of farnesoid X receptor delays, but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology. 2012. doi: 10.1002/hep.25918. [Epub ahead of print]
Ni HM, Boggess N, McGill MR, Lebofsky M, Borude P, Apte U, Jaeschke H, Ding WX. Liver Specific Loss of Atg5 Causes Persistent Activation of Nrf2 and Protects Against Acetaminophen-Induced Liver Injury. Toxicol Sci. 127:438-550, 2012 PMID: 22491424
Septer S, Edwards G, Gunewardena S, Wolfe AW, Li H, Daniel J, Apte U. Yes associated protein is involved in proliferation and differentiation in postnatal liver development. Am J Physiol Gastrointest Liver Physiol. 302:G493-G503, 2012, PMID: 22194415
Li H, Wolfe A, Septer S, Edwards G, Zhong X, Bashar Abdulkarim A, Ranganathan S, Apte U. Deregulation of Hippo kinase signaling in Human hepatic malignancies. Liver Int. 32:38-47, 2011, PMID: 22098159
Wolfe A, Thomas A, Edwards G, Jaseja R, Guo GL, Apte U. Increased Activation of Wnt/beta-catenin Pathway in Spontaneous Hepatocellular Carcinoma observed in Farnesoid X Receptor Knockout Mice. J Pharmacol Exp Ther. 338:12-21, 2011, PMID: 21430080
Limaye PB, Bowen WC, Orr A, Apte UM, Michalopoulos GK. Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation. Comp Hepatol. 9:9, 2010 PMID: 21126359Weaver BP, Zhang Y, Hiscox S, Guo GL, Apte U, Taylor KM, Sheline KT, Wang L and Andrews GK. Zip4 (Slc39a4) Expression is activated in Hepatocellular Carcinomas and Functions to Repress Apoptosis, Enhance Cell Cycle and Increase Migration. PLoS One 5 (10) pii: e13158, 2010, PMID: 20957146
Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donhamsetty S, Orr A, Monga SP, Wu WC and Michalopoulos GK. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology (May 6-Epub ahead of print) 2009.
Apte U, Thompson M, Cui S, Liu B, Zeng G, Cieply B, Monga SP. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 47:288-95, 2008.
Apte U, Zeng G, Thompson M, 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 292:G1578-85, 2007.
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.9:951-959, 2007.
Apte U M, Zeng G, Muller P, Tan X, Micsenyi A, Cipley B, Dai C, Liu Y, Kaestner KH, Monga SP. Activation of Wnt/beta-Catenin Pathway During Hepatocyte Growth Factor-Induced. Hepatology 44:992-1002, 2006.
Apte UM, Banerjee A, McRee R, Wellberg E, and Ramaiah SK. Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis. Toxicol Appl Pharmacol. 207:25-38, 2005.
Corton JC*, Apte U*, Anderson SP, Limaye P, Yoon L, Latendresse J, Dunn C, Everitt JI, Voss KA, Swanson C, Kimbrough C, Wong JS, Gill SS, Chandraratna RA, Kwak MK, Kensler TW, Stulnig TM, Steffensen KR, Gustafsson JA, and Mehendale HM. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptor. J. Biol. Chem. 279:46204-12, 2004. (* Contributed equally to this work)
Apte UM, Limaye PB, Ramaiah SK, Vaidya VS, Bucci TJ, Warbritton A, and Mehendale HM. Upregulated promitogenic signaling via cytokines and growth factors: potential mechanism of robust liver tissue repair in caloric restricted rats upon toxic challenge. Toxicol. Sci. 69:448-459, 2002.
Udayan Apte, PhD
4087 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
F: (913) 588-7501