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Nat Med. 2011 Aug 7;17(9):1101-8. doi: 10.1038/nm.2401.

Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.

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1
Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.

Abstract

Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.

PMID:
21822286
PMCID:
PMC3169707
DOI:
10.1038/nm.2401
[Indexed for MEDLINE]
Free PMC Article
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