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miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis

Abstract

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126*, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126* directly inhibit stromal cell-derived factor-1 alpha (SDF-1α) expression, and indirectly suppress the expression of chemokine (C–C motif) ligand 2 (Ccl2) by cancer cells in an SDF-1α-dependent manner. miR-126/miR-126* expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126* downregulation and poor metastasis-free survival of breast cancer patients.

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Figure 1: Identification of miR-126 and miR-126* as potential suppressors of breast cancer metastasis.
Figure 2: Identification of Sdf-1α as a target for miR-126/126*.
Figure 3: miR-126 and miR-126* regulate Sdf-1α independently.
Figure 4: miR-126/miR-126* do not suppress tumour angiogenesis or the recruitment of HSCs and EPCs.
Figure 5: miR-126/miR-126* suppress MSC migration through downregulating SDF-1α in vitro and in vivo.
Figure 6: miR-126/miR-126* regulate inflammatory monocyte recruitment through indirectly downregulating Ccl2 in vivo.
Figure 7: Epigenetic regulation of miR-126 biogenesis through changes in the methylation status of the host gene Egfl7 T2 promoter.

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Acknowledgements

The authors thank R. A. Weinberg, L. M. Wakefield, C. Counter andA. M. Pendergast for providing reagents. We also thank G. J. Markowitz for thoughtful comments on the manuscript. This work was supported by the NIH grant CA151541 to X-F.W., the S. G. Komen For The Cure Foundation grant KG101633 to X-F.W. (PI) and X.X. (Fellow), the Research Scholar Grant RSG-10-157-01-LIB from the American Cancer Society to Q-J.L. and Ministry of Science and Technology Key Program of China 2012ZX10002009-017, National Basic Research Program of China 2010CB912102 to D.X.

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Y.Z., P.Y. and X.W. designed the research; Y.Z. and P.Y. performed most experiments and analysed the results; T.S., X.X., C.L. and M.C. provided further technical assistance; D-J.L. and Y.R. provided technical assistance in luciferase reporter assay and MSCs isolation; T.I., L.M., D.A. and X.L. provided clinical samples and associated analyses; Y.Z. and X-F.W. wrote the manuscript; P.Y., D.X. and Q-J.L. edited the manuscript.

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Correspondence to Yun Zhang, Pengyuan Yang, Dong Li, Qi-Jing Li or Xiao-Fan Wang.

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Zhang, Y., Yang, P., Sun, T. et al. miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15, 284–294 (2013). https://doi.org/10.1038/ncb2690

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