miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis
Author(s)Prabhala, Harsha; Mestdagh, Pieter; Muth, Daniel; Teruya-Feldstein, Julie; Westermann, Frank; Speleman, Frank; Vandesompele, Jo; Ma, Li-Jun; Young, Jennifer J; Pan, Elizabeth; Reinhardt, Ferenc; Onder, Tamer T; Valastyan, Scott John; Weinberg, Robert A; ... Show more Show less
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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 β-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.
DepartmentBroad Institute of MIT and Harvard; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Division of Comparative Medicine
Nature Cell Biology
Ma, Li, Jennifer Young, Harsha Prabhala, Elizabeth Pan, Pieter Mestdagh, Daniel Muth, Julie Teruya-Feldstein, et al. “miR-9, a MYC/MYCN-Activated microRNA, Regulates E-Cadherin and Cancer Metastasis.” Nature Cell Biology (February 21, 2010).
Author's final manuscript