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

By M. Korpal, Brian J. Ell, F. Buffa, T. Ibrahim, M. A. Blanco, Toni Celià-Terrassa, L. Mercatali, Z. Khan, H. Goodarzi, Yuling Hua and 7 more. Nature Medicine, 2011

626 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/119e4cef5f8f4b638ac25ebef7a1efc89139a4af

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Citations in the corpus

Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, methodology): “This model has been validated in several experimental models (Beerling et al., 2016; Chaffer et al., 2006; Korpal et al., 2011; Ocaña et al., 2012; Ruscetti et al., 2015; Tsai et al., 2012).”
Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “There are also several publications confirming the relevance of MET for metastatic outgrowth (Chaffer et al , 2006; Korpal et al , 2011; Ocana et al , 2012; Tsai et al , 2012).”
EMT, MET, plasticity and tumor metastasis (2020, background): “In another study, the positive predictive value of high miR-200, an inhibitor of Zeb1 and Zeb2, for successful breast cancer metastasis was established in both mouse models and human tissues [30].”
Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “Interestingly, expression of miR-200 family members enhances the recolonization of metastatic cells, highlighting the role of this regulatory loop in maintaining the mesenchymal phenotype and demonstrating the reversibility of EMT (54).”
Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells (2013, background): “The description of signals that down-regulate EMT-TFs at the metastatic sites awaits further investigation, but it is clear that interactions between CSCs and the tumor microenvironment dictate (i) EMT and invasion of the primary tumor (73, 74) and (ii) colonization at the metastatic niche (57, 58, ”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “Indeed, such reversals by many cells within an early metastatic growth to a more epithelial state may actually be essential for metastatic colonization (Del Pozo Martin et al., 2015; Korpal et al., 2011; Ocana et al., 2012; Tsai et al., 2012).”
Epithelial–mesenchymal plasticity in carcinoma metastasis (2013, background): “Interestingly, re-expression of miR-200 family members was shown to enhance colonization possibly by repressing Sec23a-mediated secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1 (Fig.”