miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1
miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1
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DOI：
10.1038/onc.2013.108
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发表时间：
2014-03-20
期刊：
影响因子：
8
通讯作者：
Luo, Z.
中科院分区：
文献类型：
--
作者：
Wu, X.;Liu, T.;Luo, Z.
MicroRNAs(MiRNAs)通过协调抑制肿瘤相关基因的表达，越来越多地参与调节肿瘤的恶性程度。在这里，我们发现在肺癌细胞系中过表达miR-194会抑制肺癌细胞的转移，而通过miRNA海绵抑制其表达会促进癌细胞转移。在非小细胞肺癌的临床标本中，MIR-194的表达也与转移呈显著负相关。我们证明miR-194直接靶向BMP1和p27(Kip1)。BMP1的下调导致转化生长因子β活性的抑制，从而下调了关键致癌基因(基质金属蛋白酶MMP2和MMP9)的表达。这反过来又会降低肿瘤的侵袭性。此外，miRNA-194诱导的p27(Kip1)抑制激活了RhoA途径，促进了肌动蛋白应激纤维的发展，并抑制了癌细胞的迁移。这些发现揭示了调控和信号通路的两个结构独立但功能相连的分支，它们共同提供了抑制转移的miRNA和控制肺癌恶性肿瘤的关键基因之间的桥梁。
MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes. Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through miRNA sponge promotes the cancer cells to metastasize. miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer. We demonstrate that miR-194 directly targets both BMP1 and p27(kip1). The resulting downregulation of BMP1 leads to suppression of TGF beta activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9). This leads, in turn, to decreased tumor invasion. In addition, the miRNA-194-induced suppression of p27(kip1) activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells. These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers.