DF/HCC Program Affiliation

Cancer Cell Biology
Gastrointestinal Malignancies

Research Abstract

Physiologic hepatocyte proliferation, as occurs in embryos during hepatic outgrowth and in adults during liver regeneration, is a tightly regulated process. In contrast, many liver diseases are accompanied by uncontrolled hepatocyte proliferation that can lead to hepatocellular carcinoma (HCC). We believe that similar genes control hepatocyte proliferation under physiologic and pathologic settings. By identifying genes important for liver development we can probe for contribution of these factors in liver cancer development and progression. The importance of a thorough dissection of the events that control pathologic hepatocyte proliferation is underscored by the enormous burden of liver disease: chronic liver disease is currently the 12th most common cause of death in the United States. Among patients with chronic liver disease, HCC is a frequent and accompanying complication and prognosis is dire, with resection or transplantation the only curative therapies . In fact, HCC is the fifth most common cancer worldwide and the third leading cause of cancer-related death.
Our recent studies have focused on the role of the ubiquitin-like with PHD and Ringer Fingers domain protein 1 (UHRF1) in liver development, regeneration and cancer development. We have acquired zebrafish lines deficient in UHRF1 and have generated specific antibodies to UHRF1. In collaboration with Dr Kirsten Edepli at Mount Sinai School of Medicine, we have generated liver specific transgenic mutants that express wild type and a specific phosphorylation deficient mutant form of UHRF1. Our goal is to understand the role of this protein in liver cancer formation.

Publications

• Liu Z, Ukomadu C.Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant.Biochem Biophys Res Commun 2008 Jan 25;365(4):729-34.
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• Zhu W, Ukomadu C, Jha S, Senga T, Dhar SK, Wohlschlegel JA, Nutt LK, Kornbluth S, Dutta A.Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication.Genes Dev 2007 Sep 15;21(18):2288-99.
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• Sadler KC, Krahn KN, Gaur NA, Ukomadu C.Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1.Proc Natl Acad Sci U S A 2007 Jan 30;104(5):1570-5.
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• Ukomadu C, Dutta A.p21-dependent inhibition of colon cancer cell growth by mevastatin is independent of inhibition of G1 cyclin-dependent kinases.J Biol Chem 2003 Oct 31;278(44):43586-94.
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• Ukomadu C, Dutta A.Inhibition of cdk2 activating phosphorylation by mevastatin.J Biol Chem 2003 Feb 14;278(7):4840-6.
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