Hepatitis B virus (HBV) encoded x antigen (HBxAg) is a trans-activating protein that contributes to the development of hepatocellular carcinoma (HCC) by altering expression of selected hepatocellular genes. To identify some of these genes, HBxAg or vector were introduced into the human hepatoblastoma cell line, HepG2, and differentially expressed genes were identified by PCR select cDNA subtraction. Differential expression of these genes was verified by in situ hybridization (ISH) and immunohistochemistry (IHC) of HBV infected compared to uninfected liver samples. Costaining of HBxAg with several up-regulated proteins implies that each may be up-regulated by HBxAg or be a cellular response to HBxAg in vivo. To determine whether these up-regulated gene (URG) products or corresponding antibodies to them exist in serum, appropriate ELISAs were designed. In retrospective longitudinal studies, antibodies to multiple URGs were detected in the sera from 23 of 25 (>90%) of Korean carriers with HCC an average of 3 years prior to tumor diagnosis, in 18 of 24 (75%) of Korean carriers with dysplastic and/or regenerative nodules but no HCC, and in < 15% of asymptomatic carriers. Additional cross-sectional and longitudinal prospective studies in other carrier populations are required to validate these markers. Hence, the objective of this proposal will be to establish the clinical utility of these antibodies in various HBV carrier populations at risk for the development of HCC. Given that Chinese and African patients come from regions of the world with the highest incidence of HBV infection and HCC, cross-sectional (aim 1) and longitudinal (aim 2) studies will be conducted to determine whether these markers are prevalent in tumor bearing patients and/or in those at high risk for tumor development, respectively. Additional work will determine the specificity of these markers using serum samples from patients who are not HBV infected (aim 3). Antibodies to other HBxAg URGs will also be tested to optimize the sensitivity, specificity and predictive value; of the antibody panel (aim 4). This work will establish a rapid, simple, inexpensive and noninvasive blood test for early HCC that will save many lives by permiting early detection and curative intervention. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Read-Connole, Elizabeth Lee
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Temple University
Schools of Arts and Sciences
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Feitelson, Mark A; Bonamassa, Barbara; Arzumanyan, Alla (2014) The roles of hepatitis B virus-encoded X protein in virus replication and the pathogenesis of chronic liver disease. Expert Opin Ther Targets 18:293-306
Arzumanyan, A; Friedman, T; Kotei, E et al. (2012) Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene 31:563-72
Yuan, Ke; Lian, Zhaorui; Sun, Bill et al. (2012) Role of miR-148a in hepatitis B associated hepatocellular carcinoma. PLoS One 7:e35331
Wang, Wen; Zhao, Lan-Juan; Wang, Yan et al. (2011) Application of HBx-induced anti-URGs as early warning biomarker of cirrhosis and HCC. Cancer Biomark 11:29-39
Arzumanyan, Alla; Friedman, Tiffany; Ng, Irene O L et al. (2011) Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res 71:3701-8
Feitelson, Mark A; Reis, Helena M G P V; Tufan, N Lale et al. (2009) Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. Cancer Lett 286:69-79
Liu, Jie; Ahiekpor, Angela; Li, Li et al. (2009) Increased expression of ErbB-2 in liver is associated with hepatitis B x antigen and shorter survival in patients with liver cancer. Int J Cancer 125:1894-901
Cao, Wenjun; Sun, Bill; Feitelson, Mark A et al. (2009) Hepatitis C virus targets over-expression of arginase I in hepatocarcinogenesis. Int J Cancer 124:2886-92
Liu, Xiaohong; Zhang, Shuhui; Lin, Jing et al. (2008) Hepatitis B virus X protein mutants exhibit distinct biological activities in hepatoma Huh7 cells. Biochem Biophys Res Commun 373:643-7
Liu, Xiaohong; Wang, Li; Zhang, Shuhui et al. (2008) Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5a expression in hepatoma Huh7 cells: cDNA microarray and proteomic analyses. Carcinogenesis 29:1207-14

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