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  • HBV is an enveloped double stranded DNA virus which

    2021-09-18

    HBV is an enveloped, double-stranded DNA virus, which is transcripted into four major transcripts [6]. Among them, the 3.5 kb pregenomic RNA (pgRNA) directs the translation of HBV polymerase, core protein and acts as template for reverse transcription. So viral transcription is a key step of virus life cycle. The transcription of HBV mRNAs is directed by four promoters, i.e. preS1 promoter (S1p); preS2 promoter (S2p); X promoter (Xp) and core promoter (Cp). With its small genome size, HBV must utilize host factors to complete its replication. Among the host factors, several miRNAs were found to be participated in the HBV transcription [7]. For example, miRs-372/373 could enhance HBV gene expression by repressing the cellular transcription factor NFIB, which could bind directly to and negatively regulate En I/Xp activities [8]. miR-939 decreased the transcription efficiency of En II/Cp by targeting Jumonji domain containing 3 (Jmjd3) that enhanced the transcription efficiency of the promoter in a C/EBPα-dependent manner [9]. Our recent study found that miR-370 suppressed HBV gene expression and replication by targeting transcription factor NFIA, which promoted viral transcription and replication by increasing HBV En I/Xp activities [10]. However, the complex regulatory role of miRNAs in HBV replication remains to be further investigated. ELK1, a member of the ternary complex factor (TCF) subfamily of the ETS family transcription factors, is an integration point for different mitogen-activated protein (MAP) kinase pathways [11,12]. Emerging data showed that ELK1 are participated in virus life dofetilide and virus-induced diseases [[13], [14], [15]]. For example, Shi W et al. found that ELK1 was activated by MEK/ERK signaling pathway after enterovirus 71 (EV71) infection in immature dendritic cells, which play an important role in virus replication [14]. However, whether ELK1 can control HBV replication is unknown. In our previous study, we showed that several miRNAs can regulate the HBV HBsAg expression. One of these miRNAs, miR-185-5p, decreased HBsAg expression in vitro [16]. However, the specific mechanism of miR-185-5p suppressing HBV gene expression is unclear.
    Materials and methods
    Results
    Discussion HBV infection remains a major global public health problem with approximately 240 million people are chronically infected patients [17]. Chronic infection often leads to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [18,19]. The current therapies for chronic hepatitis B including interferon-α and nucleoside analogues have inhibited HBV infection to some extent but with high cost and serious side effects [20]. So it is urgent to explore the complex HBV-host interactions and to identify novel targets for HBV therapy. It has been reported that miR-185 are participated in many pathological process, especially in cancers. miR-185 could regulate tumor cell growth and invasion/migration in many cancers such as gastric cancer, breast cancer, HCC and so on [[21], [22], [23], [24]]. But whether it was involved in virus infection is largely unknown. Singaravelu R et al. found that miR-185 inhibited HCV infection by restricting the host metabolic pathways crucial to the HCV life cycle. And HCV infection decreased miR-185 to promote lipid accumulation and counteract 25-hydroxycholesterol's antiviral effect [25]. A recent report showed that the levels of miR-185 were significantly up-regulated in blood specimens from patients with HBV-liver fibrosis. Functional study showed that miR-185 targeted SREBF1 and increased expression of COL1A1 and a-SMA genes that are involved in liver fibrosis. But miR-185 was not correlated with HBV viral loads [26]. In the present study, we found that miR-185-5p plays an important role in HBV gene expression and replication in hepatoma cells. In the present study, we first examined the role of miR-185-5p in HBV transcription by testing its effect on HBV four promoters' activities. The dual luciferase assay showed that it markedly repressed S1p activities. Consistently, the proteins levels of L-HBsAg that mainly initiated by S1p was significantly decreased by miR-185-5p overexpression. The L-HBsAg is a critical component of virus envelope and is absolutely required for the correct envelopment of the HBV nucleocapsid at the membrane of the endoplasmic reticulum, and secretion of surface antigen particles and virions which are accumulated in the lumen of the endoplasmic reticulum [27,28]. So we examined the effect of miR-185-5p on HBsAg, HBeAg and HBV DNA copies in the supernatants. As expected, miR-185-5p decreased their levels in the supernatants, which is consistent with our previous findings [16]. But our previous study showed that miR-185-5p has no effect on HBeAg expression. This inconsistency may be due to the difference in detection condition. The specific mechanism for miR-185-5p-mediated HBeAg suppression needs further investigation. Moreover, the reported miRNAs that can affect HBV transcription are mainly via regulating the activities of En I/Xp, En II/Cp and S2p [7,9,10]. MiR-29c was found to decrease S1p activity by targeting TNFAIP3 [29]. MiR-141 could repress S1p activity by inhibiting the expression of peroxisome proliferator-activated receptor alpha (PPARA) [30]. In the present study, we found that miR-185-5p also decreased S1p activity, which will complex the interaction between miRNAs and the transcription from HBV S1p.