| 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 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. © 2010 Macmillan Publishers Limited. All rights reserved. |
| Keywords: |
signal transduction; vasculotropin; controlled study; vascular endothelial growth factor a; unclassified drug; human cell; nonhuman; cancer grading; neoplasms; cell proliferation; mouse; animals; mice; mus; gene overexpression; breast cancer; microrna; gene amplification; gene expression; lung neoplasms; cell line; animal experiment; animal model; protein binding; down-regulation; rna, small interfering; cancer cell culture; mice, scid; cell line, tumor; transfection; breast neoplasms; neovascularization, pathologic; uvomorulin; mice, inbred balb c; nuclear proteins; cancer invasion; lung metastasis; gene expression regulation, neoplastic; dna; neuroblastoma; messenger rna; oncogene proteins; neoplasm metastasis; micrometastasis; transplantation, heterologous; breast epithelium; epithelium cell; epithelial cells; down regulation; neoplasm invasiveness; gene dosage; micrornas; mice, inbred nod; proto-oncogene proteins c-myc; tumor vascularization; beta catenin; cadherins; histones; cell motility; 3' untranslated regions; vimentin; microrna 9; metastasis inhibition
|
