MicroRNAs in the Imprinted DLK1-DIO3 Region Repress the Epithelial-to-Mesenchymal Transition by Targeting the TWIST1 Protein Signaling Network
MicroRNAs in the Imprinted DLK1-DIO3 Region Repress the Epithelial-to-Mesenchymal Transition by Targeting the TWIST1 Protein Signaling Network
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DOI：
10.1074/jbc.m112.387761
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发表时间：
2012-12-14
影响因子：
4.8
通讯作者：
Phinney, Donald G.
中科院分区：
文献类型：
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作者：
Haga, Christopher L.;Phinney, Donald G.
转移性疾病的发展占癌症相关死亡的绝大多数。然而，很少有治疗方法被设计为特异性抑制驱动肿瘤转移的过程。印迹DLK 1-DIO 3区域包含肿瘤抑制miRNA，但它们的身份和功能仍然不确定。在这项研究中，我们在印迹DLK 1-DIO 3区域中鉴定了7种miRNA，它们协同作用以抑制上皮向间充质转化，这是驱动肿瘤转移以及癌细胞增殖的关键步骤。这七种miRNAs（miRs 300、382、494、495、539、543和544）抑制包括TWIST 1、BMI 1、ZEB 1/2和miR-200家族miRNA的信号网络并沉默簇（通过人类导管癌上游CpG岛的超甲基化发生），赋予形态学、分子学、以及与上皮细胞向间充质细胞转化一致的功能变化。此外，miR-544的异位表达通过诱导ATM细胞周期检查点途径独立地抑制许多肿瘤细胞系的增殖。这些结果确立了DLKI-DIO 3 miRNA簇作为调节肿瘤生长和转移的关键检查点，并暗示簇的表观遗传修饰驱动肿瘤进展。这些结果还表明，启动子甲基化状态和miRNA表达水平分别代表了预测和抑制癌症患者肿瘤转移的新诊断工具和治疗靶点。
Development of metastatic disease accounts for the vast majority of cancer-related deaths. Nevertheless, few treatments exist that are designed to specifically inhibit processes that drive tumor metastasis. The imprinted DLK1-DIO3 region contains tumor-suppressing miRNAs, but their identity and function remain indeterminate. In this study we identify seven miRNAs in the imprinted DLK1-DIO3 region that function cooperatively to repress the epithelial-to-mesenchymal transition, a critical step that drives tumor metastasis, as well as proliferation of carcinoma cells. These seven miRNAs (miRs 300, 382, 494, 495, 539, 543, and 544) repress a signaling network comprising TWIST1, BMI1, ZEB1/2, and miR-200 family miRNAs and silencing of the cluster, which occurs via hypermethylation of upstream CpG islands in human ductal carcinomas, confers morphological, molecular, and function changes consistent with an epithelial-to-mesenchymal transition. Moreover, ectopic expression of miR-544 independently inhibited proliferation of numerous tumor cell lines by inducing the ATM cell cycle checkpoint pathway. These results establish the DLKI-DIO3 miRNA cluster as a critical checkpoint regulating tumor growth and metastasis and implicate epigenetic modification of the cluster in driving tumor progression. These results also suggest that promoter methylation status and miRNA expression levels represent new diagnostic tools and therapeutic targets to predict and inhibit, respectively, tumor metastasis in carcinoma patients.