TY - JOUR T1 - Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. JF - Nat Med Y1 - 2011 A1 - Korpal, Manav A1 - Ell, Brian J A1 - Buffa, Francesca M A1 - Ibrahim, Toni A1 - Blanco, Mario A A1 - CeliĆ -Terrassa, Toni A1 - Mercatali, Laura A1 - Khan, Zia A1 - Goodarzi, Hani A1 - Hua, Yuling A1 - Wei, Yong A1 - Hu, Guohong A1 - Garcia, Benjamin A A1 - Ragoussis, Jiannis A1 - Amadori, Dino A1 - Harris, Adrian L A1 - Kang, Yibin KW - Animals KW - Cadherins KW - Cell Line, Tumor KW - Female KW - Gene Expression Profiling KW - Gene Expression Regulation, Neoplastic KW - HUMANS KW - Mass Spectrometry KW - Mice KW - Mice, Inbred BALB C KW - Microarray Analysis KW - MicroRNAs KW - Neoplasm Metastasis KW - Statistics, Nonparametric KW - Vesicular Transport Proteins AB -

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.

VL - 17 CP - 9 M3 - 10.1038/nm.2401 ER -