Hepatitis B Viral Insertion Generates an Oncogenic Long Noncoding RNA

Chronic hepatitis B virus (HBV) infection leads to liver inflammation and cirrhosis and is associated with significantly increased risk of hepatocellular carcinoma (HCC). The biologic consequences of HBV integration events, which often occur within or near repetitive sequences in the human genome, remain unclear, but it is possible that HBV insertion may also directly promote HCC development. Instead of focusing on changes in host gene expression at sites near viral genomic integration sites, Lau and colleagues tested whether HBV insertion events in HCC cell lines could lead to the generation of viral–human chimeric transcripts or activate the transcription of silent repetitive sequences. Most viral–human fusion transcripts did not affect expression of nearby coding genes; however, one insertion site in a noncoding region induced significant transcription of a long interspersed nuclear element 1 (LINE1) sequence by the hepatitis B protein X (HBx) promoter. This Hbx–LINE1 fusion transcript was present in 21 of 90 (23.3%) HBV-associated HCCs tested, and its presence was predictive of shorter overall survival. HBx–LINE1 expression increased risk of carcinogen-induced HCC in mice and promoted cell migration and invasion in association with epithelial-to-mesenchymal transition (EMT), further suggesting that the chimeric transcript may have functional significance. Consistent with a role in EMT, HBx–LINE1 enhanced WNT/β-catenin signaling, which is also hyperactive in a majority of HCCs. Although HBx–LINE1 encoded a protein, these effects on cell motility and β-catenin activity were unchanged by the addition of a stop codon to prevent protein translation, strongly suggesting that HBx–LINE1 functions as a long noncoding RNA. Overall, these data establish that transcription at HBV insertion sites within repetitive elements may not be a byproduct of random integration but provide a selective advantage and indicate that HBV–human chimeric transcripts may play a role in HCC pathogenesis.

Lau CC, Sun T, Ching AK, He M, Li JW, Wong AM, et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell 2014 Feb 27 [Epub ahead of print].