MiR-139-5p is associated with inflammatory regulation through c-FOS suppression, and contributes to the progression of primary biliary cholangitis
MiR-139-5p is associated with inflammatory regulation through c-FOS suppression, and contributes to the progression of primary biliary cholangitis
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DOI：
10.1038/labinvest.2016.95
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发表时间：
2016-11-01
影响因子：
5
通讯作者：
Ueno, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Katsumi, Tomohiro;Ninomiya, Masashi;Ueno, Yoshiyuki
原发性胆汁性胆管炎（PBC）是一种慢性胆汁淤积性肝病，其病理特征是肝内胆管破坏。根据临床病程，PBC 主要分为三种亚型：(i) 逐渐进行性、(ii) 门静脉高压症和 (iii) 肝衰竭。先前的研究表明，患有纤维化的 PBC 患者中促炎细胞因子 TNF-α 的血清水平升高。尽管胆管炎的严重程度也可能与 PBC 亚型有关，但其病因尚不清楚。多项研究表明 microRNA (miRNA) 在各种疾病中表现出特定的表达模式。在本研究中，我们使用综合深度测序评估了 PBC 亚型中的 miRNA 表达模式。我们还通过激光捕获显微切割进行组织学检查，并使用 miRNA 转染方法研究了鉴定的 miRNA 如何参与 PBC 临床进展。平均而言，每个样本获得了大约 1100 万个 32 聚体短 RNA 读数，我们发现 97 个 miRNA 的表达水平在四组之间存在显着差异。热图表明，肝衰竭和门静脉高压症类型的 miRNA 谱与逐渐进展型和对照的 miRNA 谱的聚类不同。此外，我们关注 miR-139-5p，它具有足够数量的总短读长。定量逆转录PCR显示，miR-139-5p在临床晚期PBC中显着下调。此外，对肝组织的检查表明，肝细胞中淋巴细胞来源的 miR-139-5p 的表达显着较高。在体外，miR-139-5p上调的细胞上清液中TNF-α的水平显着升高。此外，c-FOS 基因转录受到抑制。因此，我们证明了一种新的炎症调节机制，涉及通过 NF-κ B 信号通路中的 miR-139-5p 进行 TNF-α 和 c-FOS 转录。我们的结论是，特定的 miRNA miR-139-5p 可能参与 PBC 的发病机制，特别是在临床进展过程中。
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized pathologically by destruction of intrahepatic bile ducts. PBC is largely classified into three subtypes based on clinical course: (i) gradually progressive, (ii) portal hypertension, and (iii) hepatic failure. Previous studies have indicated that serum levels of the pro-inflammatory cytokine TNF-alpha, is elevated in PBC patients with fibrosis. Although the severity of cholangitis might also be related to the PBC subtype, its etiology has been unclear. Several studies have shown that microRNAs (miRNAs) demonstrate specific expression patterns in various diseases. In the present study, we evaluated miRNA expression patterns among the PBC subtypes using comprehensive deep sequencing. We also carried out histologic examination by laser capture microdissection and investigated how the identified miRNAs were involved in PBC clinical progression using the miRNA transfection method. On average, similar to 11 million 32-mer short RNA reads per sample were obtained, and we found that the expression levels of 97 miRNAs differed significantly among the four groups. Heat mapping demonstrated that the miRNA profiles from hepatic failure and portal hypertension type were clustered differently from those of the gradually progressive type and controls. Furthermore, we focused on miR-139-5p, which has an adequate number of total short reads. Quantitative reverse transcription PCR showed that miR-139-5p was significantly downregulated in clinically advanced PBC. Also, examination of liver tissues demonstrated that the expression of lymphocyte-derived miR-139-5p was significantly higher in hepatocytes. In vitro, the level of TNF-alpha was significantly elevated in supernatant of cells with upregulation of miR-139-5p. Furthermore, c-FOS gene transcription was repressed. Thus, we have demonstrated a novel inflammation-regulatory mechanism involving TNF-alpha and c-FOS transcription through miR-139-5p in the NF-kappa B signaling pathway. We conclude that the specific miRNA miR-139-5p might be involved in the pathogenesis of PBC, especially during clinical progression.