miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

• DOI: 10.1038/ncb2024
• Publication Date: 2010-02-21T18:24:07Z
• Authors: Li Ma; Jennifer Young; Harsha Prabhala; Elizabeth Pan; Pieter Mestdagh; Daniel Muth; Julie Teruya-Feld...; Ferenc Reinhardt; Tamer T. Onder; Scott Valastyan; Frank Westermann; Frank Speleman; Jo Vandesompele; Robert A. Weinberg
• Keywords: CDH1

MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of beta-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.