Human hepatocyte-enriched miRNA-192-3p promotes HBV replication through inhibiting Akt/mTOR signalling by targeting ZNF143 in hepatic cell lines.
Human hepatocyte-enriched miRNA-192-3p promotes HBV replication through inhibiting Akt/mTOR signalling by targeting ZNF143 in hepatic cell lines.
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富含人肝细胞的 miRNA-192-3p 通过靶向肝细胞系中的 ZNF143 抑制 Akt/mTOR 信号传导来促进 HBV 复制
DOI：
10.1080/22221751.2022.2037393
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发表时间：
2022-12
影响因子：
13.2
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Li F;Deng Y;Zhang S;Zhu B;Wang J;Wang J;Wang X;Zhao Z;Deng W;Mao R;Shen Z;Chen J;Broering R;Lin Y;Lu M;Zhang J
摘要 先前的研究已经揭示了多种组织或细胞特异性或富集的 miRNA 谱。然而，肝细胞类型中丰富的 miRNA 谱及其对 HBV 复制的影响尚未得到很好的阐明。在本研究中，从非 HBV 感染患者的肝脏标本中制备原代人肝细胞（PHH）、库普弗细胞（KC）、肝窦内皮细胞（LSEC）和肝星状细胞（HSC）。从纯化的肝细胞 miRNA 微阵列分析中鉴定出四种肝细胞类型富集的 miRNA 谱。结果显示，包括 miR-122-5p 和 miR-192-3p 在内的 12 个 miRNA 富含 PHH； 9 个 miRNA，包括 miR-142-5p 和 miR-155-5p 富含 KC； 6 个 miRNA，包括 miR-126-3p 和 miR-222-3p，富含 LSEC； 14 个 miRNA，包括 miR-214-3p 和 miR-199a-3p 富含 HSC。通过测试 11 种富含 PHH 的 miRNA 对 HBV 产生的影响，我们观察到 miR-192-3p 在肝细胞系中具有最大的前病毒作用。此外，我们进一步发现miR-192-3p通过直接靶向HepG2.2.15细胞中的ZNF143来抑制Akt/mTOR信号传导，从而促进HBV复制和基因表达。此外，慢性乙型肝炎患者血清和肝脏 miR-192-3p 表达水平显着高于健康对照，且血清 miR-192-3p 与血清 HBV DNA 和 HBsAg 水平呈正相关。总的来说，我们鉴定了四种肝细胞类型中富集的 miRNA 谱，并揭示了富含 PHH 的 miR-192-3p 通过直接靶向肝细胞系中的 ZNF143 来抑制 Akt/mTOR 信号传导，从而促进 HBV 复制。我们的研究为肝细胞类型丰富的 miRNA 在与病毒复制和各种肝脏发病机制相互作用中的作用提供了具体的视角。
ABSTRACT Previous studies have revealed multiple tissue- or cell-specific or enriched miRNA profiles. However, miRNA profiles enriched in hepatic cell types and their effect on HBV replication have not been well elucidated. In this study, primary human hepatocytes (PHHs), Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) were prepared from liver specimens of non-HBV-infected patients. Four hepatic cell type-enriched miRNA profiles were identified from purified liver cells miRNA microarray assay. The results revealed that 12 miRNAs, including miR-122-5p and miR-192-3p were PHH-enriched; 9 miRNAs, including miR-142-5p and miR-155-5p were KC-enriched; 6 miRNAs, including miR-126-3p and miR-222-3p were LSEC-enriched; and 14 miRNAs, including miR-214-3p and miR-199a-3p were HSC-enriched. By testing the effect of 11 PHH-enriched miRNAs on HBV production, we observed that miR-192-3p had the greatest pro-virus effect in hepatic cell lines. Moreover, we further found that miR-192-3p promoted HBV replication and gene expression through inhibiting Akt/mTOR signalling by direct targeting of ZNF143 in HepG2.2.15 cells. Additionally, the serum and hepatic miR-192-3p expression levels were significantly higher in chronic hepatitis B patients than in healthy controls and serum miR-192-3p positively correlated with the serum levels of HBV DNA and HBsAg. Collectively, we identified miRNA profiles enriched in four hepatic cell types and revealed that PHH-enriched miR-192-3p promoted HBV replication through inhibiting Akt/mTOR signalling by direct targeting of ZNF143 in hepatic cell lines. Our study provides a specific perspective for the role of hepatic cell type-enriched miRNA in interaction with viral replication and various liver pathogenesis.
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