Re-expression of miR-200c suppresses proliferation, colony formation and in vivo tumor growth of murine claudin-low mammary tumor cells.
Re-expression of miR-200c suppresses proliferation, colony formation and in vivo tumor growth of murine claudin-low mammary tumor cells.
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DOI：
10.18632/oncotarget.15829
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发表时间：
2017-04-04
期刊：
影响因子：
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通讯作者：
Moorehead R
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文献类型：
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作者：
Jones R;Watson K;Bruce A;Nersesian S;Kitz J;Moorehead R
克拉丁-低乳腺癌是一种相对罕见的乳腺癌亚型。这些癌症通常是ER−/PR−/HER2−，表达高水平的间充质基因以及与炎症、血管生成和干细胞功能相关的基因。除了基因表达的改变外，最近的研究表明，claudin低水平的乳腺癌表达非常低水平的miR-200 miRNAs家族。鉴于每个miRNA可以调节数十个、数百个甚至数千个基因，miRNAs正被评估为治疗靶点。在这项研究中，我们发现来自MTB-IGFIR转基因小鼠的乳腺肿瘤和来自这些肿瘤的细胞系代表了一个人低claudin乳腺癌和小鼠claudin低乳腺癌的模型，并且细胞系只表达miR-200家族的所有五个成员的极低水平。MiR-200家族表达的降低似乎是通过甲基化来调节的，因为表达低水平miR-200家族成员的细胞和肿瘤在可能的启动子区域的CpG甲基化水平高于表达高水平miR-200家族成员的肿瘤和细胞。在Claudin-low乳腺肿瘤细胞中重新表达miR-200C在体外抑制肿瘤细胞的增殖和集落形成，在体内抑制肿瘤的生长。在体内肿瘤生长方面，miR-200C的重新表达与肿瘤血管的减少以及Flt1和VEGFC的表达有关。因此，miR-200C是间叶性肿瘤细胞生长的重要调节因子。
Claudin-low breast cancer is a relatively rare breast cancer subtype. These cancers are typically ER−/PR−/HER2− and express high levels of mesenchymal genes as well as genes associated with inflammation, angiogenesis and stem cell function. In addition to alterations in gene expression, it was recently demonstrated that claudin-low breast cancers express very low levels of the miR-200 family of miRNAs. Given that each miRNA can regulate tens, hundreds or even thousands of genes, miRNAs are being evaluated as therapeutic targets. In this study we show that mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors represent a model of human claudin-low breast cancer and murine claudin-low mammary tumors and cell lines express only very low levels of all five members of the miR-200 family. Reduced miR-200 family expression appears to be regulated via methylation as cells and tumors expressing low levels of miR-200 family members had higher levels of CpG methylation in a putative promoter region than tumors and cells expressing high levels of miR-200 family members. Re-expression of miR-200c in murine claudin-low mammary tumor cells inhibited tumor cell proliferation and colony formation in vitro and tumor growth in vivo. With respect to tumor growth in vivo, re-expression of miR-200c was associated with a reduction in tumor vasculature and expression of Flt1 and Vegfc. Therefore, miR-200c is an important regulator of mesenchymal tumor cell growth.