MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis
MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis
复制标题
MicroRNA-744/转化生长因子β1关系调节肝硬化
DOI：
10.1007/s12072-019-09993-w
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发表时间：
2019-10-23
影响因子：
6.6
通讯作者：
Liu, Ping
中科院分区：
文献类型：
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作者：
Ren, Shuang;Chen, Jiamei;Liu, Ping
MicroRNA为我们理解肝硬化（LC）和相关过程（如肝星状细胞（HSC）的活化）增加了新的维度。方法收集40例LC患者和30例健康献血员的血清标本。本实验研究了CCl_4诱导的LC小鼠体内模型和体外培养的人HSC LX-2和小鼠HSC JS-1细胞。结果血清microRNA（miR）-744水平与LC的严重程度呈负相关，是LC的可靠生物标志物。在CCl 4诱导的LC模型中，与假手术对照相比，血清和肝脏中miR-744的丰度均降低。重要的是，用合成的miR-744 Agomir增加miR-744丰度减轻了肝纤维化，肝纤维化是LC的关键组分，而用Antagomir减少miR-744则加剧了肝纤维化。我们观察到miR-744和转化生长因子β 1（TGF β 1）在LC患者的血清以及来自CCl 4诱导的LC小鼠的血清/肝脏中呈负相关。我们证明了miR-744 Agomir下调TGF β 1的表达，并进一步证实TGF β 1 mRNA是HSC中真正的miR-744靶点。此外，miR-744 Agomir降低了F-actin形成和细胞增殖的程度，而miR-744 Antagomir促进了这些事件，表明miR-744是HSC活化的负调节剂。结论miR-744对HSC活化的抑制作用很可能是通过TGF β 1实现的，因为外源性TGF β 1几乎可以抵消miR-744 Agomir的作用。这项研究表明，miR-744的减少是LC的可靠生物标志物，miR-744/TGF β 1关系是LC的关键调节因子。
Background MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). Methods Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched. Results The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor beta 1 (TGF beta 1) are inversely correlated in LC patients' sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGF beta 1 and further confirmed that TGF beta 1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. Conclusions MiR-744-led suppression in HSC activation is most likely through TGF beta 1 because exogenous TGF beta 1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGF beta 1 relationship is a key regulator of LC.