title: Viral-human chimeric transcript predisposes risk to liver cancer development and progression.
abstract: 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.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Chi-Chiu
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Arthur K K
authors.initials: AK
authors.lastname: Ching
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Jing-Woei
authors.initials: JW
authors.lastname: Li
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Wong
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Ngai Na
authors.initials: NN
authors.lastname: Co
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Transgenic Facility, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Pik-Shan
authors.initials: PS
authors.lastname: Li
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Raymond W M
authors.initials: RW
authors.lastname: Lung
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Electronic address: tf.chan@cuhk.edu.hk.
authors.forename: Ting-Fung
authors.initials: TF
authors.lastname: Chan
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Electronic address: natwong@cuhk.edu.hk.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004052:Diethylnitrosamine; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D014760:Viral Fusion Proteins / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D062085:RNA, Long Noncoding; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014760:Viral Fusion Proteins; D054334:Viral Regulatory and Accessory Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; C077214:L1Hs-encoded protein p40, human; D004052:Diethylnitrosamine