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

Nature Medicine volume 17, pages 1101–1108 (2011)Cite this article

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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.

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Figure 1: miR-200s are associated with poor prognosis in breast cancer.
Figure 2: Ectopic miR-200 expression enhances spontaneous metastasis and colonization of distant organs.
Figure 3: Ectopic miR-200 expression promotes global changes in gene expression.
Figure 4: Identification of putative miR-200 targets using MS.
Figure 5: Sec23a knockdown phenocopies miR-200s in inhibiting migration and promoting metastatic colonization.
Figure 6: Sec23a knockdown disrupts secretion of proteins that are correlated with suppression of clinical metastasis.

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Acknowledgements

We thank S. Kyne at the mass spectrometry core facility, D. Storton and J. Buckles at the microarray core facility, and E. Williams at the electron microscopy facility of Princeton University for expert technical advice and support, N. Sethi for insightful discussions and blinded verification of tumor counts, S.J. Parkinson for technical advice, and K. Socha for colony counting. We also thank E. Williams (Monash Institute of Medical Research) and F. Miller (Barbara Ann Karmanos Cancer Institute) for the TSU-PR1 and 4T1 cell line series, respectively. Y.K. is a Champalimaud Investigator and a Department of Defense Era of Hope Scholar Award recipient. This research was supported by grants from the US National Institutes of Health (1R01-CA141062) and the Brewster Foundation to Y.K. and from Cancer Research UK, Oxford NHS Biomedical Research Centre and Friends of Kennington Cancer Fund to A.L.H. M.K. and Y.H. are recipients of US Department of Defense predoctoral fellowships.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA

    Manav Korpal, Brian J Ell, Mario A Blanco, Toni Celià-Terrassa, Hani Goodarzi, Yuling Hua, Yong Wei, Guohong Hu, Benjamin A Garcia & Yibin Kang

  2. Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK

    Francesca M Buffa & Adrian L Harris

  3. Osteoncology Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy

    Toni Ibrahim, Laura Mercatali & Dino Amadori

  4. Department of Cell Biology, Institut de Biologia Molecular de Barcelona, Consejo Superior de Investegaciones Cientificas, Barcelona, Spain

    Toni Celià-Terrassa

  5. Department of Computer Science, Princeton University, Princeton, New Jersey, USA

    Zia Khan

  6. The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA

    Zia Khan & Hani Goodarzi

  7. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Jiannis Ragoussis

  8. Genomic Instability and Tumor Progression Program, Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

    Yibin Kang

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Contributions

M.K. and Y.K. designed experiments. M.K., B.J.E., T.C.-T. and Y.H. performed the experiments. F.M.B., T.I., L.M., J.R., D.A. and A.L.H. provided clinical samples and associated analyses. M.A.B., Z.K., H.G., Y.W., G.H. and B.A.G. contributed genomic and proteomic analyses. M.K. and Y.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Yibin Kang.

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Korpal, M., Ell, B., Buffa, F. et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17, 1101–1108 (2011). https://doi.org/10.1038/nm.2401

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