miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4.
miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4.
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DOI：
10.1158/0008-5472.can-12-2037
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发表时间：
2013-02-15
期刊：
影响因子：
11.2
通讯作者：
Watabe K
中科院分区：
文献类型：
--
作者：
Okuda H;Xing F;Pandey PR;Sharma S;Watabe M;Pai SK;Mo YY;Iiizumi-Gairani M;Hirota S;Liu Y;Wu K;Pochampally R;Watabe K
尽管乳腺癌患者的生存率有了显著的提高，但转移性疾病的预后仍然很差。肿瘤干细胞(CSCs)被认为在乳腺癌的转移过程中起作用，然而，CSCs的确切病理作用尚不清楚。在这份报告中，我们发现从转移性乳腺细胞系分离的CSCs(CD24CD44+/EsA+)在器官特异性方面比非CSC群体更具转移性。我们对这些细胞的microRNA图谱分析结果显示，高度转移到骨和脑的CSCs表达明显较低水平的miR-7，并且这种microRNA能够调节诱导多能干细胞所必需的基因之一KLF4。有趣的是，KLF4的高表达与乳腺癌患者的脑-而不是骨转移的无转移生存期显著负相关，我们确实发现，在我们的动物模型中，miR-7的表达显著抑制了CSCs向脑转移的能力，但不抑制到骨转移的能力。我们还检测了miR-7和KLF4在脑转移瘤中的表达，发现这两个基因在脑肿瘤细胞中分别显著下调或上调。此外，我们的体外实验结果表明，miR-7通过调节KLF4的表达来减弱CSCs的侵袭和自我更新能力。提示miR-7和KLF4可能作为乳腺癌脑转移的生物标志物或治疗靶点。
Despite significant improvement in survival rates of breast cancer patients, prognosis of metastatic disease is still dismal. Cancer stem-like cells (CSCs) are considered to play a role in metastatic progression of breast cancer; however, the exact pathological role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24−/CD44+/ESA+) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ specific manner. The results of our microRNA profile analysis for these cells revealed that CSCs that are highly metastatic to bone and brain expressed significantly lower level of miR-7 and that this microRNA was capable of modulating one of the essential genes for induced pluripotent stem cell, KLF4. Interestingly, high expression of KLF4 was significantly and inversely correlated to brain- but not bone-metastasis free survival of breast cancer patients, and we indeed found that the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in our animal model. We also examined the expression of miR-7 and KLF4 in brain-metastatic lesions and found that these genes were significantly down- or up-regulated, respectively, in the tumor cells in brain. Furthermore, the results of our in vitro experiments indicate that miR-7 attenuates the abilities of invasion and self-renewal of CSCs by modulating KLF4 expression. These results suggest that miR-7 and KLF4 may serve as biomarkers or therapeutic targets for brain metastasis of breast cancer.