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

Research output: Contribution to journalArticlepeer-review

526 Scopus citations


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
Pages (from-to)1101-1109
Number of pages9
JournalNature medicine
Issue number9
StatePublished - Sep 2011


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