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

• DOI: 10.1038/nm.2401
• Publication Date: 2011-08-07T18:22:43Z
• Authors: Manav Korpal; Brian J Ell; Francesca M Buffa; Toni Ibrahim; Mario A Blanco; Toni Celià-Terrassa; Laura Mercatali; Zia Khan; Hani Goodarzi; Yuling Hua; Yong Wei; Guohong Hu; Benjamin A Garcia; Jiannis Ragoussis; Dino Amadori; Adrian L Harris; Yibin Kang
• Keywords: 0301 basic medicine; Biomedical and clinical sciences; Immunology; Vesicular Transport Proteins; Sec23a, miRNA, bioinformatics; Medical and Health Sciences; Article; Mass Spectrometry; Statistics, Nonparametric; Cell Line; Mice; 03 medical and health sciences; Cell Line, Tumor; Health Sciences; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Nonparametric; Aetiology; Neoplasm Metastasis; Inbred BALB C; Cancer; Neoplastic; Mice, Inbred BALB C; Tumor; Biomedical and Clinical Sciences; Gene Expression Profiling; Statistics; Health sciences; Cadherins; Microarray Analysis; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; Gene Expression Regulation; Female; Biotechnology

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.