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

Journal article

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. © 2011 Nature America, Inc. All rights reserved.

Authors: Korpal, M; Ell, B; Buffa, F; Ibrahim, T; Blanco, M

• Journal: Nature Medicine
• Volume: 17
• Issue: 9
• Pages: 1101-1109
• Publication date: 2011-09-01
• DOI: 10.1038/nm.2401
• EISSN: 1546-170X
• ISSN: 1078-8956
• Language: English