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.
Ma
Li
L
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Young
Jennifer
J
Prabhala
Harsha
H
Pan
Elizabeth
E
Mestdagh
Pieter
P
Muth
Daniel
D
Teruya-Feldstein
Julie
J
Reinhardt
Ferenc
F
Onder
Tamer T
TT
Valastyan
Scott
S
Westermann
Frank
F
Speleman
Frank
F
Vandesompele
Jo
J
Weinberg
Robert A
RA
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071447:N-Myc Proto-Oncogene Protein; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D006657:Histones; C541874:MIRN92 microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; D051176:beta Catenin; D004247:DNA