Viral-Human Chimeric Transcript Predisposes Risk to Liver Cancer Development and Progression

• Published in: Cancer cell Vol. 25; no. 3; pp. 335 - 349
• Main Authors: Lau, Chi-Chiu, Sun, Tingting, Ching, Arthur K.K., He, Mian, Li, Jing-Woei, Wong, Alissa M., Co, Ngai Na, Chan, Anthony W.H., Li, Pik-Shan, Lung, Raymond W.M., Tong, Joanna H.M., Lai, Paul B.S., Chan, Henry L.Y., To, Ka-Fai, Chan, Ting-Fung, Wong, Nathalie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2014
• Subjects: Animals; Base Sequence; beta Catenin - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - virology; Cell Line, Tumor; Cell Movement - genetics; Diethylnitrosamine; DNA-Binding Proteins - genetics; Epithelial-Mesenchymal Transition - genetics; Gene Expression Profiling; Hepatitis B virus; Hepatitis B virus - genetics; Humans; Liver Neoplasms - genetics; Liver Neoplasms - virology; Mice; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; Recombinant Fusion Proteins - genetics; RNA, Long Noncoding - genetics; Sequence Analysis, DNA; Trans-Activators - genetics; Transcription, Genetic - genetics; Transcriptional Activation - genetics; Transcriptome - genetics; Viral Fusion Proteins - genetics; Wnt Proteins - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.01.030

The mutagenic effect of hepatitis B (HBV) integration in predisposing risk to hepatocellular carcinoma (HCC) remains elusive. In this study, we performed transcriptome sequencing of HBV-positive HCC cell lines and showed transcription of viral-human gene fusions from the site of genome integrations. We discovered tumor-promoting properties of a chimeric HBx-LINE1 that, intriguingly, functions as a hybrid RNA. HBx-LINE1 can be detected in 23.3% of HBV-associated HCC tumors and correlates with poorer patient survival. HBx-LINE1 transgenic mice showed heightened susceptibility to diethylnitrosamine-induced tumor formation. We further show that HBx-LINE1 expression affects β-catenin transactivity, which underlines a role in activating Wnt signaling. Thus, this study identifies a viral-human chimeric fusion transcript that functions like a long noncoding RNA to promote HCC. •HBV integration into the host genome can cause transcription of viral-human chimeras•HBx-LINE1 exerts oncogenic functions as a long noncoding RNA-like transcript•HBx-LINE1 promotes tumorigenicity via activation of Wnt/β-catenin signaling•HBx-LINE1 increases risk of HCC development Lau et al. discover a viral-human fusion transcript that is detectable in a quarter of hepatitis B virus-associated hepatocellular carcinomas (HCCs). This chimeric transcript promotes HCC by functioning like a long noncoding RNA to activate the Wnt pathway.