MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2
MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2
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DOI：
10.1007/s00109-016-1441-0
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发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Ni, Chunhui
中科院分区：
文献类型：
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作者：
Han, Ruhui;Ji, Xiaoming;Ni, Chunhui
矽肺是一种致命性肺纤维化疾病，其特征是成纤维细胞和肌成纤维细胞聚集，细胞外基质蛋白沉积。MIR-449a是许多细胞过程的潜在介质，包括细胞增殖、分化和凋亡。我们推测miR-449a可能在肺纤维化的进展中起关键作用。在这里，我们描述了miR-449a作为一种新的自噬调节的miRNA。重要的是，经二氧化硅处理的小鼠肺组织中miR-449a的表达显著降低，在转化生长因子-β1刺激的NIH-3T3和MRC-5细胞中也有类似的表达。纤维化肺组织和转化生长因子-β1处理的成纤维细胞的自噬活性受到抑制。为了研究miR-449a的潜在作用，我们在小鼠模型中过表达miR-449a，发现miR-449a显著降低了二氧化硅所致肺损伤的分布和严重程度。此外，还观察到miR-449a在体内和体外均能诱导自噬活性。值得注意的是，Bcl2被确定为miR-449a的目标。MiR-449a过表达可降低NIH-3T3细胞中bcl2的表达水平。事实上，Bcl2 3‘非编码区含有功能性miR-449a反应序列。此外，还观察到转化生长因子-β1通过MAPK/ERK途径增加Bcl2的表达。这些结果表明miR-449a是一种重要的自噬调节因子，也是一种新型的内源性肺纤维化抑制因子。miR-449a在纤维化肺和活化的成纤维细胞中表达降低，在纤维化肺组织和转化生长因子-β1处理的成纤维细胞中自噬受到抑制。miR-449a在二氧化硅诱导的肺纤维化中具有抗纤维化作用。miR-449a在体外上调自噬活性。bcl2是miR-449a自噬相关的靶点。
Silicosis is a fatal pulmonary fibrotic disorder characterized by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. MiR-449a is a potential mediator of many cellular processes, including cell proliferation, differentiation, and apoptosis. We hypothesized that miR-449a may play a crucial role in the progression of pulmonary fibrogenesis. Here, we described miR-449a as a new autophagy-regulated miRNA. Importantly, miR-449a expression was significantly decreased in lung tissues of mice with silica treatment, and it was similarly expressed in NIH-3T3 and MRC-5 cells stimulated with TGF-beta 1. The activity of autophagy was inhibited in fibrotic lung tissues and TGF-beta 1-treated fibroblasts. To investigate the potential effect of miR-449a, we overexpressed miR-449a in mouse models and found that miR-449a significantly reduced both the distribution and severity of lung lesions induced by silica. In addition, miR-449a was observed to induce the activity of autophagy in vivo and in vitro. Notably, Bcl2 was identified as a target of miR-449a. Bcl2 levels were decreased in NIH-3T3 cells upon miR-449a overexpression. Indeed, the Bcl2 3' UTR contained functional miR-449a responsive sequences. Furthermore, TGF-beta 1 was observed to increase the expression of Bcl2 via the MAPK/ERK pathway. These results suggest that miR-449a is an important regulator of autophagy, as well as a novel endogenous suppressor of pulmonary fibrosis.MiR-449a expression was decreased in fibrotic lungs and activated fibroblasts.Autophagy was inhibited in fibrotic lung tissues and TGF-beta 1-treated fibroblasts.MiR-449a had an antifibrotic effect in silica-induced lung fibrosis.MiR-449a upregulated autophagic activity in vitro.Bcl2 is the autophagy-related target of miR-449a.