Viral-human chimeric transcript predisposes risk to liver cancer development and progression

Chi-Chiu Lau; Tingting Sun; Arthur K K Ching; Mian He; Jing-Woei Li; Alissa M Wong; Ngai Na Co; Anthony W H Chan; Pik-Shan Li; Raymond W M Lung; Joanna H M Tong; Paul B S Lai; Henry L Y Chan; Ka-Fai To; Ting-Fung Chan; Nathalie Wong

doi:10.1016/j.ccr.2014.01.030

Viral-human chimeric transcript predisposes risk to liver cancer development and progression

Cancer Cell. 2014 Mar 17;25(3):335-49. doi: 10.1016/j.ccr.2014.01.030. Epub 2014 Feb 27.

Authors

Affiliations

¹ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
² 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.
³ Transgenic Facility, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
⁴ Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
⁵ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
⁶ 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.
⁷ School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Electronic address: tf.chan@cuhk.edu.hk.
⁸ 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.

PMID: 24582836
DOI: 10.1016/j.ccr.2014.01.030

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / virology
Cell Line, Tumor
Cell Movement / genetics
DNA-Binding Proteins / genetics*
Diethylnitrosamine
Epithelial-Mesenchymal Transition / genetics
Gene Expression Profiling
Hepatitis B virus / genetics
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / virology
Mice
Mice, Transgenic
Molecular Sequence Data
Promoter Regions, Genetic
RNA, Long Noncoding / genetics
Recombinant Fusion Proteins / genetics
Sequence Analysis, DNA
Trans-Activators / genetics*
Transcription, Genetic / genetics
Transcriptional Activation / genetics
Transcriptome / genetics
Viral Fusion Proteins / genetics*
Viral Regulatory and Accessory Proteins
Wnt Proteins / metabolism
Wnt Signaling Pathway / genetics
beta Catenin / metabolism

Substances

DNA-Binding Proteins
RNA, Long Noncoding
Recombinant Fusion Proteins
Trans-Activators
Viral Fusion Proteins
Viral Regulatory and Accessory Proteins
Wnt Proteins
beta Catenin
hepatitis B virus X protein
L1Hs-encoded protein p40, human
Diethylnitrosamine

Associated data

SRA/SRP023539