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

• Published in: Nature cell biology Vol. 12; no. 3; pp. 247 - 256
• Main Authors: Vandesompele, Jo, Young, Jennifer, Weinberg, Robert A, Muth, Daniel, Westermann, Frank, Prabhala, Harsha, Speleman, Frank, Pan, Elizabeth, Onder, Tamer T, Mestdagh, Pieter, Reinhardt, Ferenc, Teruya-Feldstein, Julie, Valastyan, Scott, Ma, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2010; Nature Publishing Group
• Subjects: 3' Untranslated Regions - genetics; 631/208/200; 631/337/384/331; 631/67/322; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biology; Biomedical and Life Sciences; Brain cancer; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cancer Research; Cell Biology; Cell Line; Cell Line, Tumor; Cell Proliferation; Development and progression; Developmental Biology; DNA - metabolism; Down-Regulation - genetics; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Dosage; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - physiology; Genetic aspects; Histones - metabolism; Humans; Invasiveness; Life Sciences; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; MicroRNA; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - physiology; Motility; N-Myc Proto-Oncogene Protein; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplasms - blood; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neuroblastoma - diagnosis; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncogenes; Physiological aspects; Protein Binding - genetics; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Small Interfering - genetics; Signal Transduction - physiology; Stem Cells; Transfection; Transplantation, Heterologous - pathology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor A - genetics; Vimentin - metabolism; United States; New York; United States > US; Massachusetts
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2024

miRNAs can both promote and repress tumorigenesis, and directly control epithelial–mesenchymal transition (EMT). miR-9 (which is upregulated in breast cancer cells) is activated by MYC and MYCN, and regulates EMT and metastasis through direct control of E-cadherin. In contrast, tumour angiogenesis is controlled indirectly through effects on vascular endothelial growth factor (VEGF) expression. 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.