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

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

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425 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1101-1109
Number of pages9
JournalNature Medicine
Volume17
Issue number9
DOIs
StatePublished - Sep 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Korpal, M., Ell, B. J., Buffa, F. M., Ibrahim, T., Blanco, M. A., Celià-Terrassa, T., Mercatali, L., Khan, Z., Goodarzi, H., Hua, Y., Wei, Y., Hu, G., Garcia, B. A., Ragoussis, J., Amadori, D., Harris, A. L., & Kang, Y. (2011). Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nature Medicine, 17(9), 1101-1109. https://doi.org/10.1038/nm.2401