Ourania Andrisani, MD, PHD
Active Mentor – currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees
Current Research Interests:
My research interests and expertise are on molecular mechanisms of transcriptional regulation, epigenetics, and signal transduction involved in cell growth control, cellular differentiation and cancer pathogenesis. My laboratory studies epigenetic mechanisms involved in Hepatitis B virus (HBV) biosynthesis and virus-mediated hepatocarcinogenesis. Our ongoing studies focus on cellular factors regulating both virus biosynthesis and formation of hepatic cancer stem cells (hCSCs). Our goal is to identify essential mechanisms that can be targeted to suppress HBV infection and the resulting HBV-mediated liver cancer. One such mechanism identified by our studies is activation of the cellular S/T kinase Polo-like-kinase 1 (Plk1) by the virus-encoded oncogenic HBx protein. We have shown that Plk1 activation exerts a crucial role both as a positive effector of HBV replication and HBV-mediated oncogenic transformation. In collaboration with the team of Professor Philippe Merle, M.D., Ph.D., Medical Co-Director of the Liver Department at Lyon University Hospital, France, we have shown that HBV infection, via Plk1, deregulates an epigenetic mechanism that alters stability and function of the Polycomb Repressive complex 2 (PRC2). This deregulation involves downregulation of the RNA helicase DDX5, which interacts with PRC2 and the noncoding RNA HOTAIR to repress transcription of specific genes. Interestingly, we have identified re-expression of select DDX5/PRC2 repressed genes in liver tumors associated with poor patient prognosis. These genes include markers of hCSCs and pluripotency genes, referred to as the hCSC-like gene signature. Importantly, we have evidence that DDX5 becomes downregulated, via HBV-mediated induction of two oncomiRs, miR17-92 and miR106b-25. Interestingly, HBV replicating cells with knockdown of DDX5 exhibit resistance to chemotherapy drugs, including sorafenib. Sorafenib is the only available treatment for advanced liver cancer but it only prolongs patient life by few months, because of resistance. Our ongoing studies have identified a likely mechanism contributing to sorafenib insensitivity of the DDX5-knockdown cell lines, which involves escape from a non-apoptotic cell death called ferroptosis. Our goal is to test this hypothesis, and develop a preclinical model of liver cancer to interfere with this pathway in vivo.
Selected Publications:
Wang WH, Studach L, and Andrisani O. (2011) Proteins ZNF198 and SUZ12 are down-regulated in Hepatitis B Virus (HBV) X protein mediated hepatocyte transformation and in HBV replication. Hepatology, 53:1137-47. PMCID: PMC3079326
Studach L, Menne S, Cairo S, Buendia MA, Hullinger RL, LeFrancois L, Merle P and Andrisani O. (2012) Subset of Suz12/PRC2 target genes is activated during HBV replication and liver carcinogenesis associated with HBV X protein. Hepatology, 56:1240-51. PMCID: PMC3417088
Zhang H, Diab A, Fan H, Mani S, Hullinger R, Merle P, and Andrisani O. (2015) Polo-like-kinase1 and long noncoding RNA HOTAIR accelerate proteasomal degradation of SUZ12 and ZNF198, downregulated in Hepatitis B Virus hepatocarcinogenesis. Cancer Research,75:2363-2374 PMID: 25855382 PMCID: PMC4452430
Fan H, Zhang H, Pascuzzi P, and Andrisani O. (2016) Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene 11; 35(6):715-26 PMID: 25893293. PMCID:PMC4615262
Mani, S. K. Zhang, H. Diab, A. Pascuzzi, P. E. Lefrancois, L. Fares, N. Bancel, B. Merle, P. Andrisani, O. (2016) EpCAMRegulated Intramembrane Proteolysis Induces a Cancer Stem Cell-like Gene Signature in Hepatitis B Virus-infected Hepatocytes. J Hepatol, 65:888-898 PMID 27238755 PMCID: PMC5289705 Editorial: Stemness of liver cancer: From hepatitis B virus to Wnt activation Journal of Hepatology, Volume 65, Pages 888-898
Zhang H, Xing Z, Mani S, Bancel B, Durantel D, Zoulim F, Tran E, Merle P, and Andrisani O. (2016) RNA helicase DDX5 regulates PRC2/HOTAIR function in Hepatitis B virus infection and hepatocarcinogenesis. Hepatology, 64:1033-48 PMID: 2733802 PMCID: PMC5033702
Fan, H, Zhang, H. Mani, S, Diab, A, Merle, P. and Andrisani, O. DNA demethylation induces SALL4 gene expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene, 2017 27;36 (17):2435-2445. PMID: 27797380 PMCID: PMC5408304
Diab AM, Foca A, Fusil F, Lahlali T, Jalaguier P, Amirache F, N’Guyen L, Isorce N, Cosset FL, Zoulim F, Andrisani O*, Durantel D*. Polo-like-kinase 1 is a proviral host-factor for hepatitis B virus replication. Hepatology, 66:1750-1765 (2017) * cocorersponding authors PMID: 28445592 Editorial: Polo-like-kinase1: A key cellular target for anti-HBV therapy? Lai, MC, Hepatology 66, 1750, 2017
Diab A, Foca A, Zoulim F, Durantel D, Andrisani, O. The diverse functions of the hepatitis B core/capsid protein (HBc) in the viral life cycle: Implications for the development of HBc-targeting antivirals. Antiviral Res, 2018, in press
Mani SSK and Andrisani O. Hepatitis B Virus Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells. Genes (Basel), 2018 Mar 2;9(3). pii: E137. doi:10.3390/genes9030137. PMID: 29498629 (INVITED REVIEW)
