Chronic Hepatitis B Virus (HBV) infection is a major factor in the pathogenesis of hepatocellular carcinoma (HCC). Despite the HBV vaccine, the World Health Organization reports 400 million people are chronically infected with HBV. Current treatments are ineffective, and rates of primary HCC have tripled in the U.S. from 1975-2005. To reduce liver cancer, new and effective therapies are needed, as well as new biomarkers for molecular classification and prognosis of the disease. In this proposal we investigate the role of the mitotic Polo-like kinase1 (Plk1) in the pathogenesis of HBV-mediated liver cancer (HBV-HCC). Pathogenesis of HBV-HCC involves chronic liver inflammation and effects of the weakly oncogenic HBV X protein (pX). pX activates cellular mitogenic pathways, promotes DNA re-replication-induced DNA damage and activates Plk1. In turn, Plk1 mediates checkpoint adaptation, generating partial polyploidy in non- transformed pX-expressing hepatocytes. Significantly, inhibition of Plk1 suppresses pX-mediated transformation. However much remains to be understood about the role of Plk1 in pX-mediated transformation and HBV-HCC. Toward this end, we have identified by a genome-wide siRNA library screen, SUZ12 and ZNF198 as tumor suppressors of pX-mediated transformation. Our results indicate that these proteins are negatively regulated by Plk1. Both in human liver cancer cell lines and tissues from chronic HBV patients with HCC, protein levels of Plk1 are increased, whereas those of SUZ12 and ZNF198 are reduced relative to normal controls. This inverse relationship (high protein levels of Plk1 and reduced levels of SUZ12 &ZNF198) also occurs during HBV replication, suggesting overexpression of Plk1 and down-regulation of SUZ12 &ZNF198 is important both for transformation and HBV replication. SUZ12 and ZNF198 mediate chromatin remodeling and associate with PML nuclear bodies (NBs) that regulate DNA repair, apoptosis and viral replication. We reason down-regulation of SUZ12 &ZNF198 by Plk1 alters hepatocyte gene expression and disrupts the function of PML NBs. Accordingly, our hypothesis is: Plk1 down-regulates SUZ12 and ZNF198, which enhances HBV replication by disrupting PML NBs, and mediates oncogenic transformation by deregulating hepatocyte gene expression. We will investigate in Aim 1, the role of Plk1, SUZ12, and ZNF198 in pX-mediated transformation and HBV replication;
in Aim 2, the mechanism by which Plk1 down-regulates ZNF198 and SUZ12.
In Aim 3, we will investigate whether protein levels of Plk1, SUZ12, ZNF198, and expression of known SUZ12 target genes are prognostic for disease progression and survival. Impact: High level of viremia in chronic HBV patients is a risk factor for progression to HCC. Inhibition of Plk1 could serve as a therapy strategy to suppress HBV replication, reducing the risk of HCC development. Plk1 inhibitors are in clinical trials for other types of cancer and could serve as therapy for HBV-HCC. Our studies hold promise to reveal novel therapy targets and biomarkers for HBV-HCC.

Public Health Relevance

Liver cancer has the fastest growing death rate in the US, relative to other cancers;chronic Hepatitis B Virus infection is a major factor for liver cancer development. New and effective therapies and biomarkers are needed. Our studies aim to identify new therapies and biomarkers for HBV-mediated liver cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CE-M (09))
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Sherker, Averell H
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Purdue University
Other Basic Sciences
Schools of Veterinary Medicine
West Lafayette
United States
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Diab, Ahmed; Foca, Adrien; Zoulim, Fabien et al. (2018) 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 149:211-220
Mani, Saravana Kumar Kailasam; Andrisani, Ourania (2018) Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells. Genes (Basel) 9:
Mani, Saravana Kumar Kailasam; Andrisani, Ourania (2018) Interferon signaling during Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma. Cytokine :
Zhang, Hao; Zhang, Yanqiu; Zhu, Xiaoyun et al. (2018) DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1. Hepatology :
Diab, Ahmed; Foca, Adrien; Fusil, Floriane et al. (2017) Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication. Hepatology 66:1750-1765
Fan, H; Cui, Z; Zhang, H et al. (2017) DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene 36:2435-2445
Mani, Saravana Kumar Kailasam; Zhang, Hao; Diab, Ahmed et al. (2016) EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol 65:888-898
Fan, H; Zhang, H; Pascuzzi, P E et al. (2016) Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene 35:715-26
Zhang, Hao; Xing, Zheng; Mani, Saravana Kumar Kailasam et al. (2016) RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis. Hepatology 64:1033-48
Zhang, Hao; Diab, Ahmed; Fan, Huitao et al. (2015) PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis. Cancer Res 75:2363-74

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