MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.
MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.
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MicroRNA100 抑制乳腺癌干细胞的自我更新和乳腺肿瘤的发展
DOI：
10.1158/0008-5472.can-13-3710
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Deng L;Shang L;Bai S;Chen J;He X;Martin-Trevino R;Chen S;Li XY;Meng X;Yu B;Wang X;Liu Y;McDermott SP;Ariazi AE;Ginestier C;Ibarra I;Ke J;Luther T;Clouthier SG;Xu L;Shan G;Song E;Yao H;Hannon GJ;Weiss SJ;Wicha MS;Liu S
MiRNAs通过调控干细胞关键调控基因的表达，对正常和恶性干细胞的自我更新和分化起着至关重要的作用。在这里，我们报告了miR100与癌症干细胞(CSC)自我更新有关的证据。我们发现miR100的表达水平与细胞的分化状态有关，在显示干细胞标记的细胞中表达最低。利用四环素诱导的慢病毒在人类细胞中上调miR100的表达，我们发现增加miR100水平会减少乳腺CSCs的产生。这种作用与抑制体外和小鼠移植瘤中癌细胞的增殖有关，这是由于CSC调节基因SMARCA5、SMARCD1和BMPR2的表达减弱所致。此外，在乳腺CSCs原位种植或心内注射后立即诱导miR100可以完全阻止肿瘤的生长和转移形成。临床上，我们观察到乳腺癌标本中miR100的表达与患者生存期之间存在显著的相关性。我们的结果提示，miR100是指导CSC自我更新和分化所必需的。
miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem-like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation.