Ma Li, Teruya-Feldstein Julie, Weinberg Robert A
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Nature. 2007 Oct 11;449(7163):682-8. doi: 10.1038/nature06174. Epub 2007 Sep 26.
MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.
微小RNA参与调控多种细胞通路。尽管越来越多的证据表明某些微小RNA可发挥癌基因或肿瘤抑制基因的作用，但微小RNA在介导癌症转移中的作用仍未得到探索。在此，我们利用小鼠和人类细胞相结合的方法表明，微小RNA - 10b（miR - 10b）在转移性乳腺癌细胞中高度表达，并正向调节细胞迁移和侵袭。在原本不具有转移能力的乳腺肿瘤中过表达miR - 10b会引发强烈的侵袭和转移。miR - 10b的表达由转录因子Twist诱导，Twist直接结合到mir - 10b（MIRN10B）的假定启动子上。由Twist诱导产生的miR - 10b进而抑制编码同源盒D10的信使核糖核酸的翻译，导致一个已被充分研究的促转移基因RHOC的表达增加。值得注意的是，原发性乳腺癌中miR - 10b的表达水平与临床进展相关。这些发现提示了一种未被描述的调控途径的作用机制，即一个多效性转录因子诱导特定微小RNA的表达，该微小RNA抑制其直接靶标，进而激活另一个促转移基因，导致肿瘤细胞侵袭和转移。
