Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Regulates Host Gene PPM1A Related to Hepatocellular Carcinoma

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Author(s): Tanit Chavalit, Pattaraporn Nimsamer, Kritsada Khongnomnan, Songtham Anuntakarun, Suthat Saengchoowong, Pisit Tangkijvanich, Sunchai Payungporn*.

Journal Name: MicroRNA

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Background: Hepatitis B is a liver infected disease caused by the hepatitis B virus (HBV) that can become chronic and develop to the hepatocellular carcinoma. HBV was classified as a double-stranded DNA virus. Currently, there is a report showing that HBV virus-encoded miRNA called HBV-miR-3 which control in the replication of HBV. However, the regulation of HBV-miR-3 to host cells remains unclear.

Objective: This study aimed to investigate the regulation of HBV-miR-3 in host gene target which related to chronic HBV infection and HCC process.

Method: In this study, we analysed the read count of HBV-miR-3 from next-generation sequencing of chronic hepatitis patients in Pegylated interferon alpha-2a (PEG-IFN-α-2a) treatment. To understanding the regulation of HBV-miR-3 in host cells, the HBV-miR-3 recognition sizes were predicted in host target genes using miRDB. The effect of HBV-miR-3 in host cells were examined using qPCR and 3′ UTR dual luciferase assay.

Results: The read count of HBV-miR-3 was found in chronic hepatitis patients before treatment. Moreover, the decreasing of HBV-miR-3 was correlated response group of chronic hepatitis patients after treatment. On the other hand, the abundance of HBV-miR-3 showed no difference in non-response group of chronic patients after PEG-IFN-α-2a treatment. To study the role of HBV-miR-3 in patients, the four HBV-miR-3 target regions from Protein phosphatase 1A (PPM1A) and DIX domain containing 1 (DIXDC1) were identified in the human genome using miRDB. Interestingly, we found that HBV-miR-3 hybridized with PPM1A mRNA. The mRNA expression from RT-qPCR showed no different between HepG2 transfected with pSilencer_scramble or pSilencer_HBV-miR-3. However, the reporter assay showed that PPM1A mRNA was suppressed by HBV-miR-3. The protein expression of PPM1A showed decreasing in cell overexpressing HBV-miR-3. Finally, the HBV-miR-3 can promote cell proliferation in cell overexpressing HBV-miR-3.

Conclusion: This study is the first report showed the HBV encoded miRNA can regulate host gene expression. HBV-miR-3 silenced PPM1A by inhibiting the translation process of PPM1A. The downregulation of PPM1A promotes cell proliferation related to HCC development.

Keywords: HBV-miR-3, miRNA, PPM1A, HCC, HepG2 cells, infection

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(E-pub Ahead of Print)
DOI: 10.2174/2211536608666191104105334

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