MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis
MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis
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DOI：
10.1016/j.stem.2014.10.001
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发表时间：
2014-12-04
期刊：
影响因子：
23.9
通讯作者：
Kamoub, Antoine E.
中科院分区：
文献类型：
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作者：
Cuiffo, Benjamin G.;Campagne, Antoine;Kamoub, Antoine E.
间充质干细胞/基质细胞（MSC）是参与乳腺肿瘤基质形成并促进转移的祖细胞。尽管人们对乳腺癌细胞 (BCC) 对乳腺恶性肿瘤的影响的认识不断加深，但乳腺癌细胞 (BCC) 对 MSC 影响的潜在分子反应仍不完全清楚。在这里，我们发现 MSC 会导致 microRNA 的异常表达，这种异常表达在 microRNA-199a 的引导下，为 BCC 提供了增强的癌症干细胞 (CSC) 特性。我们证明，这种 MSC 失调的 microRNA 构成了一个网络，该网络会聚并抑制 FOXP2 的表达，FOXP2 是一种与语音和语言发展密切相关的叉头转录因子。 BCC 中 FOXP2 敲低足以促进 CSC 增殖、肿瘤发生和转移。重要的是，microRNA-199a 表达水平升高和 FOXP2 表达水平降低是恶性临床乳腺癌的显着特征，并且与较差的生存率显着相关。我们的结果确定了癌症进展的分子决定因素，在乳腺癌的预后和治疗中具有潜在的用途。
Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.