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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

Authors

  • 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

Journal

Nature cell biology

Publication Data

March 1, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: K99 CA138572
  • Agency: NCI NIH HHS, Id: K99 CA138572-01

Mesh Terms

  • 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