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The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis

Abstract

MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that are important in many biological processes1,2. Although the oncogenic and tumour-suppressive functions of several miRNAs have been characterized, the role of miRNAs in mediating tumour metastasis was addressed only recently3 and still remains largely unexplored4,5. To identify potential metastasis-promoting miRNAs, we set up a genetic screen using a non-metastatic, human breast tumour cell line that was transduced with a miRNA-expression library and subjected to a trans-well migration assay. We found that human miR-373 and miR-520c stimulated cancer cell migration and invasion in vitro and in vivo, and that certain cancer cell lines depend on endogenous miR-373 activity to migrate efficiently. Mechanistically, the migration phenotype of miR-373 and miR-520c can be explained by suppression of CD44. We found significant upregulation of miR-373 in clinical breast cancer metastasis samples that correlated inversely with CD44 expression. Taken together, our findings indicate that miRNAs are involved in tumour migration and invasion, and implicate miR-373 and miR-520c as metastasis-promoting miRNAs.

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Figure 1: Identification of human miRNAs that induce cell migration and invasion.
Figure 2: Human miR-373 and miR-520c promote tumour metastasis in vivo.
Figure 3: Direct suppression of CD44 is required for miR-373 metastasis-promoting function.
Figure 4: Endogenous expression of miR-373 is required for invasive phenotype.
Figure 5: miR-373 expression in clinical breast cancer specimens.

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References

  1. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 287–297 (2004).

    Article  Google Scholar 

  2. Plasterk, R. H. A. MicroRNAs in animal development. Cell 124, 877–881 (2006).

    Article  CAS  Google Scholar 

  3. Ma, L., Teruya-Feldstein, J., Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).

    Article  CAS  Google Scholar 

  4. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

    Article  CAS  Google Scholar 

  5. Esquela-Kerscher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).

    Article  CAS  Google Scholar 

  6. Fidler, I. J. The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nature Rev. Cancer 3, 1–6 (2003).

    Article  Google Scholar 

  7. Steeg, P. S. 2006. Tumour metastasis: mechanistic insights and clinical challenges. Nature Rev. Med. 12, 895–904 (2006).

    Article  CAS  Google Scholar 

  8. Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    Article  CAS  Google Scholar 

  9. Du, T. & Zamore, P. D. microPrimer: the biogenesis and function of microRNA. Development 132, 4645–4652 (2005).

    Article  CAS  Google Scholar 

  10. He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004).

    Article  CAS  Google Scholar 

  11. Carthew, R. W. Gene regulation by microRNA. Curr. Opin. Gene Dev. 16, 203–208 (2006).

    Article  CAS  Google Scholar 

  12. Filipowicz, W. RNAi: The nuts and bolts of the RISC machine. Cell 122, 17–20 (2005).

    Article  CAS  Google Scholar 

  13. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  Google Scholar 

  14. Hwang, H. -W. & Mendel, J. T. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Brit. J. Cancer 94, 776–780 (2006).

    Article  CAS  Google Scholar 

  15. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  Google Scholar 

  16. Hazan, R. B., Phillips, G. R., Qiao, R. F., Norton, L. & Aaronson, S. A. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion and metastasis. J. Cell Biol. 148, 779–790 (2000).

    Article  CAS  Google Scholar 

  17. Mukhina, S. et al. Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc. Natl Acad. Sci. USA 101, 15166–15171 (2004).

    Article  CAS  Google Scholar 

  18. Voorhoeve, P. M. et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124, 1169–1181 (2006).

    Article  CAS  Google Scholar 

  19. Bentwich, I. et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genet. 37, 766–770 (2005).

    Article  CAS  Google Scholar 

  20. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).

    Article  CAS  Google Scholar 

  21. Takahashi, Y. et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 11, 1380–1385 (2005).

    Article  CAS  Google Scholar 

  22. Sasak, M., Tsuneyama, K. & Nakanuma, K. Aberrant expression of trefoil factor family 1 in biliary epithelium in hepatolithiasis and cholangiocarcinoma. Lab. Invest. 83, 1403–1413 (2003).

    Article  Google Scholar 

  23. Ren, J. L., Luo, J. Y., Lu, Y. P., Wang, L. & Shi, H. X. Relationship between trefoil factor 1 expression and gastric mucosa injuries and gastric cancer. World J. Gastroenterol. 11, 2674–2677 (2005).

    Article  CAS  Google Scholar 

  24. Fei, P. et al. Bnip3L is induced by p53 under hypoxia and its knockdown promotes tumor growth. Cancer Cell 6, 597–609 (2004).

    Article  CAS  Google Scholar 

  25. Ponta, H., Sherman, L. & Herrlich, P. A. CD44, from adhesion molecules to signalling regulators. Nature Rev. Mol. Cell Biol. 4, 33–45 (2003).

    Article  CAS  Google Scholar 

  26. Diaz, L.K. et al. CD44 expression is associated with increased survival in node-negative invasive breast carcinoma. Clin. Cancer Res. 11, 3309–3314 (2005).

    Article  CAS  Google Scholar 

  27. Berner, H.S. et al. Clinicopathological associations of CD44 mRNA and protein expression in primary breast carcinomas. Histopathol. 42, 546–554 (2003).

    Article  CAS  Google Scholar 

  28. Gong, Y., Sun, X., Huo, L., Wiley, E. L. & Rao, M. S. Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel density in invasive micropapillary carcinoma of the breast. Histopathol. 46, 24–30 (2005).

    Article  CAS  Google Scholar 

  29. Jaeger, E. B., Samant, R. S. & Rinker-Schaeffer, C. W. Metastasis suppression in prostate cancer. Cancer Metastasis Rev. 20, 279–286 (2001).

    Article  CAS  Google Scholar 

  30. Choi, S. H. et al. CD44s expression in human colon carcinoma influences growth of liver metastases. Int. J. Cancer 85, 523–526 (2000).

    Article  CAS  Google Scholar 

  31. Pereira, P.A. et al. CD44s expression mitigates the phenotype of human colorectal cancer hepatic metastases. Anticancer Res. 21, 2713–2717.

  32. Lopez, J. I. et al. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res. 65, 6755–6763 (2005).

    Article  CAS  Google Scholar 

  33. Cichy, J. et al. Proteinase-mediated release of epithelial cell-associated CD44. J. Biol. Chem. 277, 44440–44447 (2002).

    Article  CAS  Google Scholar 

  34. Cichy, J. & Puré, E. Oncostatin M and transforming growth factor-β1 induce post-translational modification and hyaluronan binding to CD44 in lung-derived epithelial tumor cells. J. Biol. Chem. 275, 18061–18069 (2000).

    Article  CAS  Google Scholar 

  35. Blenkiron, C. et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 8, R214 (2007).

    Article  Google Scholar 

  36. Gumireddy, K. et al. An in vivo selection for metastasis promoting genes in the mouse. Proc. Natl Acad. Sci. USA 104, 6696–6701 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Janet Price (The University of Texas, MD Anderson Cancer Center, Houston, TX) for providing the MDA-MB-435 cell line, Ron Kerkhoven and Mike Heimerikx (Netherlands Cancer Institute, Amsterdam) for assistance in using the array facility, Roderick Beijersbergen (Netherlands Cancer Institute, Amsterdam) for establishing the high-throughput-screening facility and Louise Showe, Celia Chang and Wenhai Horng (The Wistar Institute) for microarray analysis. Q.H. is supported by Breast Cancer Alliance, Pardee Foundation, V Foundation and Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health. R.A. is supported by the Dutch Cancer Society (KWF), the European Young Investigator Award (EURYI), the Dr Josef Steiner Cancer Research Foundation and the EMBO Young Investigator Program. G.C. and L.Z. are supported by the Netherlands Cancer Institute Ovarian Cancer Research fund and the American Cancer Society.

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Correspondence to Qihong Huang or Reuven Agami.

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Huang, Q., Gumireddy, K., Schrier, M. et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10, 202–210 (2008). https://doi.org/10.1038/ncb1681

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