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MicroRNA expression profile in response to CDM-3008 treatment in human hepatocytes.

ABSTRACT: Chronic hepatitis B virus (HBV) infections represent a significant global health burden requiring effective therapeutic interventions. This study investigates the antiviral potential of microRNAs (miRNAs) targeting the HBV entry receptor, sodium-taurocholate cotransporting polypeptide (NTCP). Using an interferon (IFN) alpha analog, we highlighted a set of miRNAs induced in treated human hepatocytes. Notably, miR-29b-1-5p was predicted to interact with the 3’-untranslated region (3’-UTR) of NTCP. Functional analysis revealed that miR-29b-1-5p directly targeted and inhibited NTCP. Furthermore, miR-29b-1-5p overexpression significantly reduced HBV genome levels in infected hepatocytes. A rescue experiment demonstrated that miR-29b-1-5p antiviral effect was specifically mediated by NTCP targeting. In summary, these findings underscore the therapeutic potential of miR-29b-1-5p against HBV, advocating for the exploration of miRNA-based therapies in the treatment of human viral infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264652 | GEO | 2024/04/26

REPOSITORIES: GEO

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Project description:Chronic hepatitis B virus (HBV) infections remain a health burden affecting ~250 million people worldwide. Thus far, available interferon-alpha (IFNα)-based therapies have shown unsatisfactory cure rates, and alternative therapeutic molecules are still required. However, their development has been hampered because accessible cell models supporting relevant HBV replication and appropriate antiviral activity are lacking. Strategies that reverse epigenetic alterations offer a unique opportunity for cell reprogramming, which is valuable for restoring altered cellular functions in human cell lines. This work aimed to investigate the feasibility of converting HepG2 cells that stably overexpress the HBV entry receptor (sodium/taurocholate cotransporting polypeptide, NTCP) toward IFNα-responsive cells using epigenetic reprogramming. Herein, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine restored the anti-HBV action of IFNα in epigenetically reprogrammed HepG2-NTCP-C4 cells, named REP-HepG2-NTCP cells. Thus, a significant inhibition in HBV DNA levels was measured in REP-HepG2-NTCP cells after IFNα treatment. This inhibitory effect was associated with the enhancement of IFNα-mediated induction of critical interferon-stimulated genes (ISGs), which was limited in non-reprogrammed cells. In particular, our data indicated that re-expression of 2’-5’-oligoadenylate synthetase 1 (OAS1) and interferon regulatory factor 9 (IRF9) was the result of an epigenetically driven unmasking of these genes in reprogrammed cells. At last, we evaluated the therapeutic potential of the IFN analog CDM-3008 in REP-HepG2-NTCP cells and demonstrated the efficiency of this chemical compound in triggering ISG induction and HBV inhibition. In summary, this study shows that epigenetic reprogramming promotes the IFNα response in HBV-infected cells and is potentially attractive for cell-based experimental screening of IFN-like compounds.

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MicroRNA expression profile in response to CDM-3008 treatment in human hepatocytes.

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