Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7.

Akemi Takata,Kazuhiko Koike,Motoko Ohno,Motoyuki Otsuka,Takeshi Yoshikawa,Takahiro Kishikawa

doi:10.1038/srep23237

Akemi Takata, Kazuhiko Koike + Show 4 more

Open Access

https://doi.org/10.1038/srep23237

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Abstract

The interplay between viral and host factors plays a major role in viral pathogenesis. Hepatitis B virus (HBV) infection is a global health problem that leads to liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV proteins have been studied extensively about their implication in hepatocarcinogenesis, the molecular mechanisms of oncogenesis are still largely unknown. A recent concept in gene regulation, in which competitive endogenous RNAs compete for common microRNAs (miRNAs), suggests that mRNA targets are key elements in the regulation of miRNA availability. Here, we show that HBV mRNA in the preS2 region can be targeted by host miRNA let-7 g. This leads to the sequestration of let-7 g and inhibition of let-7 g function. The expression of HBV transcripts, including the preS2 region, de-repressed let-7 g targets, which may contribute to long-term oncogenesis. HBV transcript-expressing transgenic mice, but not non-targeted transcript-expressing mice, were more prone to chemically induced hepatoocarcinogenesis. Let-7 target protein expression was upregulated in human HCC tissues derived from HBV-infected patients. On the other hand, let-7 g inhibited HBV preS2 protein expression and viral products. These results suggest that the interplay between viral intermediate transcripts during HBV replication and host miRNAs is crucial to the pathogenesis of chronic viral infection.

Highlights

While several sequences were selected as candidates, sequences in the Hepatitis B virus (HBV) preS2 region of the HBV large S antigen had the highest probability according to another confirmatory search using the RNA22 database (Supplementary Figure 1)
While frequent deletion of the preS region was reported, in cases with hepatocellular carcinoma (HCC)[22,23,24], we confirmed that such deletions usually occur at the terminal of preS1 and starting regions of preS2, which do not overlap with the let-7 g targeting sequences (Fig. 1f)
We describe that sequences in HBV preS2 region can be targeted by cellular let-7 g, resulting in the impaired function of this miRNA through the decreased intrinsic recruitment of the miRNA into Ago2-related complexes

Summary

Introduction

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs. Mature miRNAs are recruited into the Ago2-related RNA-induced silencing complex (RISC) and act as suppressors of gene expression. Pseudogenes had been recognized as defunct relatives of known genes, some pseudogenes, such as the phosphatase and tensin homology deleted on chromosome ten (PTEN) pseudogenes, have been recently reported as biologically functional. These decoys consume copies of the miRNAs, de-repressing PTEN and enhancing its tumor suppressor activity[5]. Closed circular HBV DNA (cccDNA) is formed by conversion from rcDNA after HBV infection and exists persistently in the hepatocyte nucleus in an episomal state, where it acts as a viral transcription template. We determined whether host cellular miRNAs possibly interacting with the viral RNA may interfere the HBV replication

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