1. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.
- Author
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Korpal, Manav, 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, Korpal, Manav, 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
- 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