miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.
Journal:
Nat. Cell Biol. 2010 MarAuthors:
Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S, Westermann F, Speleman F, Vandesompele J, Weinberg RA
Abstract
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
...[more] 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.[less]
Mesh Headings:
3' Untranslated Regions, Animals, Breast Neoplasms, Cadherins, Cell Line, Cell Line, Tumor, Cell Proliferation, DNA, Down-Regulation, Epithelial Cells, Female, Gene Dosage, Gene Expression, Gene Expression Regulation, Neoplastic, Histones, Humans, Lung Neoplasms, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, MicroRNAs, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Protein Binding, Proto-Oncogene Proteins c-myc, RNA, Small Interfering, Signal Transduction, Transfection, Transplantation, Heterologous, Vascular Endothelial Growth Factor A, Vimentin, beta Catenin