miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.
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.
Pubmed ID: 20173740 RIS Download
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