Hepatitis C virus core protein-induced miR-93-5p up-regulation inhibits interferon signaling pathway by targeting IFNAR1.
Hepatitis C virus core protein-induced miR-93-5p up-regulation inhibits interferon signaling pathway by targeting IFNAR1.
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丙型肝炎病毒核心蛋白诱导的miR-93-5p上调通过靶向IFNAR1抑制干扰素信号通路
DOI：
10.3748/wjg.v24.i2.226
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发表时间：
2018-01-14
影响因子：
4.3
通讯作者：
Mao Q
中科院分区：
文献类型：
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作者：
He CL;Liu M;Tan ZX;Hu YJ;Zhang QY;Kuang XM;Kong WL;Mao Q
探讨丙型肝炎病毒（HCV）核心蛋白诱导的miR-93- 5 p上调对干扰素（IFN）信号通路的调控机制。用pcDNA3.1（+）载体在Huh 7细胞中表达HCV-1b核心蛋白。采用定量逆转录-聚合酶链反应和Western blot检测miR-93- 5 p和干扰素受体1（IFNAR 1）的表达。Western blot检测STAT 1蛋白表达及磷酸化水平。分别使用miR-93 - 5 p agomir和iFNAR 1 siRNA以及pcDNA3.1-IFNAR 1和IFNAR 1 siRNA进行miR-93 - 5 p和IFNAR 1的过表达和沉默。荧光素酶测定用于鉴定IFNAR 1是否是miR-93- 5 p的靶标。还进行了细胞实验。与健康受试者相比，HCV-1b感染患者血清miR-93- 5 p水平升高，HCV-1b清除后降至正常水平，但在聚乙二醇干扰素-α耐药患者中持续升高。血清miR-93- 5 p表达的AUC值为0.8359，用于区分聚乙二醇化干扰素-α耐药患者和聚乙二醇化干扰素-α敏感性患者。HCV-1b核心蛋白增加Huh 7细胞中miR-93- 5 p的表达并诱导IFN信号通路失活。此外，IFNAR 1被鉴定为miR-93- 5 p的直接靶点，并且IFNAR 1恢复可以挽救miR-93- 5 p减少的STAT 1磷酸化，这表明miR-93- 5 p-IFNAR 1轴调节IFN信号通路。HCV-1b核心蛋白诱导的miR-93- 5 p上调通过直接靶向IFNAR 1抑制IFN信号通路，miR-93- 5 p-IFNAR 1轴调节STAT 1磷酸化。该轴可能是HCV-1b感染的潜在治疗靶点。
To investigate the mechanism by which hepatitis C virus (HCV) core protein-induced miR-93-5p up-regulation regulates the interferon (IFN) signaling pathway. HCV-1b core protein was exogenously expressed in Huh7 cells using pcDNA3.1 (+) vector. The expression of miR-93-5p and interferon receptor 1 (IFNAR1) was measured using quantitative reverse transcription-polymerase chain reaction and Western blot. The protein expression and phosphorylation level of STAT1 were evaluated by Western blot. The overexpression and silencing of miR-93-5p and IFNAR1 were performed using miR-93-5p agomir and antagomir, and pcDNA3.1-IFNAR1 and IFNAR1 siRNA, respectively. Luciferase assay was used to identify whether IFNAR1 is a target of miR-93-5p. Cellular experiments were also conducted. Serum miR-93-5p level was increased in patients with HCV-1b infection and decreased to normal level after HCV-1b clearance, but persistently increased in those with pegylated interferon-α resistance, compared with healthy subjects. Serum miR-93-5p expression had an AUC value of 0.8359 in distinguishing patients with pegylated interferon-α resistance from those with pegylated interferon-α sensitivity. HCV-1b core protein increased miR-93-5p expression and induced inactivation of the IFN signaling pathway in Huh7 cells. Furthermore, IFNAR1 was identified as a direct target of miR-93-5p, and IFNAR1 restore could rescue miR-93-5p-reduced STAT1 phosphorylation, suggesting that the miR-93-5p-IFNAR1 axis regulates the IFN signaling pathway. HCV-1b core protein-induced miR-93-5p up-regulation inhibits the IFN signaling pathway by directly targeting IFNAR1, and the miR-93-5p-IFNAR1 axis regulates STAT1 phosphorylation. This axis may be a potential therapeutic target for HCV-1b infection.
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