Novel pre-mRNA splicing of intronically integrated HBV generates oncogenic chimera in hepatocellular carcinoma

Yung Tuen Chiu, John K.L. Wong, Shing Wan Choi, Karen M.F. Sze, Daniel W.H. Ho, Lo Kong Chan, Joyce M.F. Lee, Kwan Man, Stacey Cherny, Wan Ling Yang, Chun Ming Wong*, Pak Chung Sham, Irene O.L. Ng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background & Aims Hepatitis B virus (HBV) integration is common in HBV-associated hepatocellular carcinoma (HCC) and may play an important pathogenic role through the production of chimeric HBV-human transcripts. We aimed to screen the transcriptome for HBV integrations in HCCs. Methods Transcriptome sequencing was performed on paired HBV-associated HCCs and corresponding non-tumorous liver tissues to identify viral-human chimeric sites. Validation was further performed in an expanded cohort of human HCCs. Results Here we report the discovery of a novel pre-mRNA splicing mechanism in generating HBV-human chimeric protein. This mechanism was exemplified by the formation of a recurrent HBV-cyclin A2 (CCNA2) chimeric transcript (A2S), as detected in 12.5% (6 of 48) of HCC patients, but in none of the 22 non-HCC HBV-associated cirrhotic liver samples examined. Upon the integration of HBV into the intron of the CCNA2 gene, the mammalian splicing machinery utilized the foreign splice sites at 282 nt. and 458 nt. of the HBV genome to generate a pseudo-exon, forming an in-frame chimeric fusion with CCNA2. The A2S chimeric protein gained a non-degradable property and promoted cell cycle progression, demonstrating its potential oncogenic functions. Conclusions A pre-mRNA splicing mechanism is involved in the formation of HBV-human chimeric proteins. This represents a novel and possibly common mechanism underlying the formation of HBV-human chimeric transcripts from intronically integrated HBV genome with functional impact. Lay summary HBV is involved in the mammalian pre-mRNA splicing machinery in the generation of potential tumorigenic HBV-human chimeras. This study also provided insight on the impact of intronic HBV integration with the gain of splice sites in the development of HBV-associated HCC.

Original languageEnglish
Pages (from-to)1256-1264
Number of pages9
JournalJournal of Hepatology
Volume64
Issue number6
DOIs
StatePublished - 1 Jun 2016
Externally publishedYes

Funding

FundersFunder number
Lee Shiu Family Foundation
Research Grants Council General Research Fund17116414
SK Yee Medical Research Fund
Health and Medical Research Fund12111092, 13120932

    Keywords

    • Cyclin A2
    • HBV integration
    • Hepatocellular carcinoma
    • Splicing

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