Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1.
Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1.
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DOI：
10.1038/srep22141
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发表时间：
2016-02-25
影响因子：
4.6
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Ge J;Chang N;Zhao Z;Tian L;Duan X;Yang L;Li L
RNA结合蛋白HuR介导转化生长因子β1诱导的促纤维化作用鞘氨醇激酶1（SphK 1）的上调参与了TGF-β1诱导的肝星状细胞（HSC）活化在肝纤维化中的作用。但TGF-β1调控SphK 1的分子机制尚不清楚。本研究旨在探讨HuR在TGF-β1诱导的SphK 1表达中的作用，并探讨其在肝纤维化中的新的分子机制。在体内，HuR的表达增加，易位到细胞质，并结合到SphK 1 mRNA在四氯化碳和胆管结扎诱导的小鼠肝纤维化。HuR mRNA表达与SphK 1 mRNA表达呈正相关，与纤维化标志物α-平滑肌肌动蛋白（α-SMA）和胶原α1（I）mRNA表达呈正相关。在体外，SphK 1的上调和TGF-β1刺激的HSC活化依赖于HuR在细胞质中的积累。抑制HuR表达或阻断HuR胞质转位可减弱TGF-β1的作用。同时，HuR的过表达模拟了TGF-β1的作用。TGF-β1通过促进SphK 1与HuR的结合延长SphK 1 mRNA的半衰期。药理学或siRNA诱导的SphK 1抑制废除HuR介导的HSC激活。结论：HuR与SphK 1 mRNA结合，在TGF-β1诱导的HSC活化中起重要作用。
RNA-binding protein HuR mediates transforming growth factor (TGF)-β1-induced profibrogenic actions. Up-regulation of Sphingosine kinase 1 (SphK1) is involved in TGF-β1-induced activation of hepatic stellate cells (HSCs) in liver fibrogenesis. However, the molecular mechanism of TGF-β1 regulates SphK1 remains unclear. This study was designed to investigate the role of HuR in TGF-β1-induced SphK1 expression and identify a new molecular mechanism in liver fibrogenensis. In vivo, HuR expression was increased, translocated to cytoplasm, and bound to SphK1 mRNA in carbon tetrachloride- and bile duct ligation-induced mouse fibrotic liver. HuR mRNA expression had a positive correlation with mRNA expressions of SphK1 and fibrotic markers, α-smooth muscle actin (α-SMA) and Collagen α1(I), respectively. In vitro, up-regulation of SphK1 and activation of HSCs stimulated by TGF-β1 depended on HuR cytoplasmic accumulation. The effects of TGF-β1 were diminished when HuR was silenced or HuR cytoplasmic translocation was blocked. Meanwhile, overexpression of HuR mimicked the effects of TGF-β1. Furthermore, TGF-β1 prolonged half-life of SphK1 mRNA by promoting its binding to HuR. Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC activation. In conclusion, our data suggested that HuR bound to SphK1 mRNA and played a crucial role in TGF-β1-induced HSC activation.