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

作者：Korpal Manav; Ell Brian J; Buffa Francesca M; Ibrahim Toni; Blanco Mario A; Celia Terrassa Toni; Mercatali Laura; Khan Zia; Goodarzi Hani; Hua Yuling; Wei Yong; Hu Guohong; Garcia Benjamin A; Ragoussis Jiannis; Amadori Dino; Harris Adrian L; Kang Yibin^*

来源：Nature Medicine, 2011, 17(9): 1101-U108.

DOI：10.1038/nm.2401

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.

• 出版日期2011-9