Neoplastic transformation of intra- and extra-hepatic biliary epithelial cells (cholangiocytes), gives rise to cholangiocarcinoma, a devastating cancer that has a very poor prognosis. Early diagnosis is difficult as symptoms usually arise as a result of bile duct blockage and relative resistance to current chemotherapies makes for a short life expectancy after diagnosis. Therefore, research into the control of cholangiocarcinoma cell growth is imperative to design more effective treatment strategies. We have obtained novel preliminary data indicating that there is an over production of the growth factor progranulin in cholangiocarcinoma cells and tissue and thus, suggest that this factor may play a role in the progression of cholangiocarcinoma. The overall objective of this proposal is to determine the molecular mechanisms by which progranulin is upregulated and to determine the consequences of increased progranulin production on cell growth. Our proposed work will focus on two specific aims that have been designed to test the following hypotheses: 1) Progranulin is upregulated in cholangiocarcinoma as a result of aberrant IL-6 expression via an ERK1/2/RSK/C/EBP(-dependent pathway. 2) Progranulin has growth promoting properties on cholangiocarcinoma via the IP3/Ca2?dependent inhibition of FOXO1 transcriptional activity. The elucidation of the mechanism by which progranulin production is increased in cholangiocarcinoma and the consequences of the increased progranulin levels on cholangiocarcinoma cell growth will be important in understanding the etiology of cholangiocarcinoma and may play a paramount role in the development of therapeutic strategies for the treatment of cholangiocarcinoma.

Public Health Relevance

Cholangiocarcinoma is a devastating cancer of the biliary tract that has poor prognosis and limited treatment options. The health relatedness of this application is that dissecting the mechanisms that may be responsible for the malignant transformation of cholangiocytes (cells that line the biliary tree) into cholangiocarcinoma can ultimately be expected to provide understanding of the causes of cholangiocarcinoma and increase opportunities for the development of novel treatment regimes for the treatment of this deadly cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Texas A&M University
Internal Medicine/Medicine
Schools of Medicine
College Station
United States
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Huang, Li; Chen, Wei; Liang, Peiwen et al. (2015) Serum CYFRA 21-1 in Biliary Tract Cancers: A Reliable Biomarker for Gallbladder Carcinoma and Intrahepatic Cholangiocarcinoma. Dig Dis Sci 60:1273-83
Demorrow, Sharon (2013) Progranulin: a novel regulator of gastrointestinal cancer progression. Transl Gastrointest Cancer 2:145-151
Leyva-Illades, Dinorah; Demorrow, Sharon (2013) Orphan G protein receptor GPR55 as an emerging target in cancer therapy and management. Cancer Manag Res 5:147-55
DeMorrow, Sharon; Meng, Fanyin; Venter, Julie et al. (2013) Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms. Am J Physiol Gastrointest Liver Physiol 305:G250-7
Huang, Li; Frampton, Gabriel; Rao, Arundhati et al. (2012) Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events. Lab Invest 92:1451-60
Frampton, Gabriel; Invernizzi, Pietro; Bernuzzi, Francesca et al. (2012) Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut 61:268-77
Frampton, Gabriel; Ueno, Yoshiyuki; Quinn, Matthew et al. (2012) The novel growth factor, progranulin, stimulates mouse cholangiocyte proliferation via sirtuin-1-mediated inactivation of FOXO1. Am J Physiol Gastrointest Liver Physiol 303:G1202-11
Leyva-Illades, Dinorah; McMillin, Matthew; Quinn, Matthew et al. (2012) Cholangiocarcinoma pathogenesis: Role of the tumor microenvironment. Transl Gastrointest Cancer 1:71-80
Huang, Li; Ramirez, Jonathan C; Frampton, Gabriel A et al. (2011) Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor. Lab Invest 91:1007-17
Huang, Li; Quinn, Matthew A; Frampton, Gabriel A et al. (2011) Recent advances in the understanding of the role of the endocannabinoid system in liver diseases. Dig Liver Dis 43:188-93

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