Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways.
Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways.
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DOI：
10.1158/0008-5472.can-16-1571
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Kim J;Siverly AN;Chen D;Wang M;Yuan Y;Wang Y;Lee H;Zhang J;Muller WJ;Liang H;Gan B;Yang X;Sun Y;You MJ;Ma L
许多人类肿瘤的侵袭和转移特性与 microRNA miR-10b 的上调有关，但其在这种情况下的功能贡献尚未完全阐明。在这里，我们报告了 miR-10b 缺陷小鼠的产生，其中 miR-10b 被证明对于正常发育很大程度上是可有可无的，但对于肿瘤发生至关重要。在转移性乳腺癌小鼠模型中，miR-10b 的缺失可延迟癌基因诱导的乳腺肿瘤发生并抑制上皮间质转化、内渗和转移。在miR-10b的靶基因中，抑癌基因Tbx5和Pten以及转移抑制基因Hoxd10因miR-10b缺失而显着上调。从机制上讲，miR-10b 通过抑制转录因子 TBX5 的表达来促进乳腺癌细胞增殖、迁移和侵袭，从而抑制抑癌基因 DYRK1A 和 PTEN。在乳腺癌临床标本中，TBX5、HOXD10 和 DYRK1A 的表达与患者的无复发生存期和总生存期结果相关。我们的结果将 miR-10b 确定为一种驱动转移的 oncomiR，称为 metastamiR，并定义了它克服的一组关键肿瘤抑制机制，以驱动乳腺癌进展。
The invasive and metastatic properties of many human tumors have been associated with upregulation of the microRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here we report the generation of miR-10b-deficient mice in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN. In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression.