1. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization
- Author
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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, and Kang, Yibin
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Genetics ,Cancer ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Cadherins ,Cell Line ,Tumor ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Humans ,Mass Spectrometry ,Mice ,Mice ,Inbred BALB C ,MicroRNAs ,Microarray Analysis ,Neoplasm Metastasis ,Statistics ,Nonparametric ,Vesicular Transport Proteins ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - 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.
- Published
- 2011