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

The miR200 family regulates EMT through E-cadherin modulation and has been proposed to contribute to metastasis thusly. This report identifies a promoting role of miR-200 in metastatic colonization that involves a novel target, the tumor secretome. The correlation between miR-200 and metastasis in p...

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Bibliographic Details
Published in:Nature medicine Vol. 17; no. 9; pp. 1101 - 1108
Main Authors: Korpal, Manav, Ell, Brian J, Buffa, Francesca M, Ibrahim, Toni, Blanco, Mario A, Celià-Terrassa, Toni, Mercatali, Laura, Khan, Zia, Goodarzi, Hani, Hua, Yuling, Wei, Yong, Hu, Guohong, Garcia, Benjamin A, Ragoussis, Jiannis, Amadori, Dino, Harris, Adrian L, Kang, Yibin
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.09.2011
Nature Publishing Group
Subjects:
631/337/384/331
631/67/322
631/80/79/1902
692/699/67/1347
Animals
Biomedical and Life Sciences
Biomedicine
Breast cancer
Cadherins - metabolism
Cancer
Cancer Research
Cell adhesion & migration
Cell Line, Tumor
Colonization
Female
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic - physiology
Humans
Infectious Diseases
Mass Spectrometry
Metabolic Diseases
Metastasis
Mice
Mice, Inbred BALB C
Microarray Analysis
MicroRNAs - metabolism
Molecular Medicine
Neoplasm Metastasis - physiopathology
Neurosciences
Proteins
Statistics, Nonparametric
Vesicular Transport Proteins - metabolism
United States
ISSN:1078-8956, 1546-170X, 1546-170X
Online Access:Get full text
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Summary:The miR200 family regulates EMT through E-cadherin modulation and has been proposed to contribute to metastasis thusly. This report identifies a promoting role of miR-200 in metastatic colonization that involves a novel target, the tumor secretome. The correlation between miR-200 and metastasis in people with cancer supports the relevance of this biphasic, multifaceted role of miR-200. 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.
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ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/nm.2401