SCARNA10, a nuclear-retained long non-coding RNA, promotes liver fibrosis and serves as a potential biomarker
SCARNA10, a nuclear-retained long non-coding RNA, promotes liver fibrosis and serves as a potential biomarker
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SCARNA10是一种核保留的长非编码RNA，可促进肝纤维化并可作为潜在的生物标志物
DOI：
10.7150/thno.32935
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Hong, Wei
中科院分区：
文献类型：
--
作者：
Zhang, Kun;Han, Yawei;Hong, Wei
长链非编码RNA（lncRNA）参与多种生物学功能和病理过程。然而，lncRNA的临床意义及其在肝纤维化中的功能在很大程度上仍不清楚。研究方法：采用实时定量RT-PCR方法检测晚期肝纤维化患者血清和肝组织、两种肝纤维化小鼠模型肝组织以及培养的肝星状细胞（HSC）中lncRNA SCARNA 10的转录水平。慢病毒介导的SCARNA 10敲低或过表达在肝纤维化中的作用在体外和体内进行了检查。进一步探讨SCARNA 10的下调或过表达对TGFβ通路相关基因表达的影响及其机制。结果如下：基因芯片结果显示lncRNA ENSMUST 00000158992（Scarna 10）在小鼠肝纤维化组织中表达显著上调。我们观察到SCARNA 10在晚期肝纤维化患者的血清和肝脏中的转录增加。此外，我们发现SCARNA 10通过诱导肝细胞（HC）凋亡和HSC活化促进肝纤维化。RNA免疫沉淀（RIP）分析表明SCARNA 10与多梳抑制复合物2（PRC 2）物理相关。另外，SCARNA 10通过抑制PRC 2与ECM和TGFβ通路相关基因启动子的结合，从而促进这些基因的转录，在肝纤维化中发挥TGFβ信号正调控作用。结论：我们的研究确定了SCARNA 10在肝纤维化中的关键作用，证明了该分子作为一种潜在的诊断标志物和一种可能的治疗靶点。
Long non-coding RNAs (lncRNAs) are involved in numerous biological functions and pathological processes. However, the clinical significance of lncRNAs and their functions in liver fibrosis remain largely unclear. Methods: The transcript of lncRNA SCARNA10 in serum and liver samples from patients with advanced hepatic fibrosis, liver tissues from two fibrosis mouse models, and cultured hepatic stellate cells (HSCs) was determined by real-time RT-PCR. The effects of lentivirus-mediated knockdown or over-expression of SCARNA10 in liver fibrosis were examined in vitro and in vivo. Moreover, the effects and mechanisms of down-regulation or over-expression of SCARNA10 on the expression of the genes involved in TGFβ pathway were determined. Results: It was found lncRNA ENSMUST00000158992, named as Scarna10, was remarkably up-regulated in mouse fibrotic livers according to the microarray data. We observed that the transcript of SCARNA10 was increased in the serum and liver from patients with advanced hepatic fibrosis. Furthermore, we found that SCARNA10 promoted liver fibrosis both in vitro and in vivo through inducing hepatocytes (HCs) apoptosis and HSCs activation. Mechanistically, RNA immunoprecipitation (RIP) assays demonstrated that SCARNA10 physically associated with polycomb repressive complex 2 (PRC2). Additionally, our results demonstrated that SCARNA10 functioned as a novel positive regulator of TGFβ signaling in hepatic fibrogenesis by inhibiting the binding of PRC2 to the promoters of the genes associated with ECM and TGFβ pathway, thus promoting the transcription of these genes. Conclusions: Our study identified a crucial role of SCARNA10 in liver fibrosis, providing a proof of this molecule as a potential diagnostic marker and a possible therapeutic target against liver fibrosis.