Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Cancer Res. 2010 Jun 15;70(12):5147-54. doi: 10.1158/0008-5472.CAN-10-0410. Epub 2010 Jun 8.
miR-31 inhibits breast cancer metastasis via the pleiotropic suppression of a cohort of prometastatic target genes that include integrin alpha(5) (ITGA5), radixin (RDX), and RhoA. We previously showed that the concomitant overexpression of ITGA5, RDX, and RhoA was capable of overriding the antimetastatic effects of ectopically expressed miR-31 in vivo. However, these prior studies failed to investigate whether the combined suppression of the endogenous mRNAs encoding these three proteins recapitulated the in vivo consequences of miR-31 expression on metastasis. We show here that short hairpin RNA-mediated concurrent downregulation of ITGA5, RDX, and RhoA is sufficient to phenocopy the full spectrum of described influences of miR-31 on metastasis in vivo, including the effects of this microRNA (miRNA) on local invasion, early post-intravasation events, and metastatic colonization. These findings provide mechanistic insights into the metastatic process and have implications about the importance of pleiotropy for the biological actions of miRNAs.
miR-31 通过抑制包括整合素 α5（ITGA5）、radixin（RDX）和 RhoA 在内的一组促转移靶基因的多效性来抑制乳腺癌转移。我们之前表明，ITGA5、RDX 和 RhoA 的共表达能够在体内逆转异位表达的 miR-31 的抗转移作用。然而，这些先前的研究未能研究这三种蛋白质的内源性 mRNA 的联合抑制是否重现了 miR-31 表达对转移的体内后果。我们在这里表明，短发夹 RNA 介导的 ITGA5、RDX 和 RhoA 的同时下调足以模拟 miR-31 对体内转移的全部描述影响，包括这种 miRNA 对局部侵袭、早期入侵后事件和转移定植的影响。这些发现为转移过程提供了机制上的见解，并表明多效性对于 miRNA 的生物学作用的重要性。
