Cyclin D1 is a major target of miR-206 in cell differentiation and transformation
Cyclin D1 is a major target of miR-206 in cell differentiation and transformation
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DOI：
10.4161/cc.26674
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发表时间：
2013-12-15
期刊：
影响因子：
4.3
通讯作者：
Grossi, Milena
中科院分区：
文献类型：
--
作者：
Alteri, Alessandra;De Vito, Francesca;Grossi, Milena
miR-206是myomiR家族的一员，被广泛认为是骨骼肌分化的特异性正调控因子。越来越多的证据也表明miR-206的肿瘤抑制功能，因为它在各种类型的癌症中经常下调。在这项研究中，我们发现miR-206直接靶向细胞周期蛋白D1，并有助于调节肌源性和非肌肉转化细胞中的CCND 1基因表达。我们证明，miR-206，无论是外源性或内源性，降低细胞周期蛋白D1的水平和C2 C12细胞的增殖率，而不促进分化，并在终末分化的C2 C12细胞中的miR-206敲低导致细胞周期蛋白D1在肌管中的积累，表明miR-206可能参与有丝分裂后状态的维持。细胞周期蛋白D1的靶向作用也可能至少部分地解释了先前研究中对miR-206的肿瘤抑制活性的提示。因此，对肿瘤和匹配的正常肺组织的分析揭示，在大多数情况下，肺肿瘤中的miR-206下调与较高的细胞周期蛋白D1水平相关。此外，癌症衍生细胞系和体外转化细胞的功能获得性实验表明，miR-206介导的细胞周期蛋白D1抑制与生长抑制直接相关。总之，我们的数据突出了miR-206在骨骼肌分化中的新活性，并将细胞周期蛋白D1确定为进一步加强miR-206的肿瘤抑制功能的主要靶点。
miR-206, a member of the so-called myomiR family, is largely acknowledged as a specific, positive regulator of skeletal muscle differentiation. A growing body of evidence also suggests a tumor suppressor function for miR-206, as it is frequently downregulated in various types of cancers. In this study, we show that miR-206 directly targets cyclin D1 and contributes to the regulation of CCND1 gene expression in both myogenic and non-muscle, transformed cells. We demonstrate that miR-206, either exogenous or endogenous, reduces cyclin D1 levels and proliferation rate in C2C12 cells without promoting differentiation, and that miR-206 knockdown in terminally differentiated C2C12 cells leads to cyclin D1 accumulation in myotubes, indicating that miR-206 might be involved in the maintenance of the post-mitotic state. targeting of cyclin D1 might also account, at least in part, for the tumor-suppressor activity suggested for miR-206 in previous studies. Accordingly, the analysis of neoplastic and matched normal lung tissues reveals that miR-206 downregulation in lung tumors correlates, in most cases, with higher cyclin D1 levels. Moreover, gain-of-function experiments with cancer-derived cell lines and with in vitro transformed cells indicate that miR-206-mediated cyclin D1 repression is directly coupled to growth inhibition. Altogether, our data highlight a novel activity for miR-206 in skeletal muscle differentiation and identify cyclin D1 as a major target that further strengthens the tumor suppressor function proposed for miR-206.