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miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1

Oncogene volume 33, pages 1506–1514 (2014)Cite this article

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Abstract

MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes. Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through ‘miRNA sponge’ promotes the cancer cells to metastasize. miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer. We demonstrate that miR-194 directly targets both BMP1 and p27kip1. The resulting downregulation of BMP1 leads to suppression of TGFβ activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9). This leads, in turn, to decreased tumor invasion. In addition, the miRNA-194-induced suppression of p27kip1 activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells. These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics. CA Cancer J Clin 2008; 58: 71–96.

    Article  Google Scholar 

  2. Zhang S, Chen W, Kong L, Li L, Lu F, Li G et al. An analysis of cancer incidence and mortality from 30 cancer registries in China, 1998-2002. Bull Chin Cancer 2006; 16: 430–448.

    Google Scholar 

  3. D’Amico TA . Molecular biologic staging of lung cancer. Ann Thorac Surg 2008; 85: s737–s742.

    Article  Google Scholar 

  4. Harpole DH . Prognostic modeling in early stage lung cancer: an evolving process from histopathology to genomics. Thorac Surg Clin 2007; 17: 67–73.

    Article  Google Scholar 

  5. Gupta GP, Massague J . Cancer metastasis: building a framework. Cell 2006; 127: 679–695.

    Article  CAS  Google Scholar 

  6. Fidler IJ . The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3: 453–458.

    Article  CAS  Google Scholar 

  7. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  Google Scholar 

  8. Garzon R, Croce CM . MicroRNAs in normal and malignant hematopoiesis. Curr Opin Hematol 2008; 15: 352–358.

    Article  CAS  Google Scholar 

  9. Ventura A, Jacks T . MicroRNAs and cancer: short RNAs go a long way. Cell 2009; 136: 586–591.

    Article  CAS  Google Scholar 

  10. Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 2009; 137: 1032–1064.

    Article  CAS  Google Scholar 

  11. Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA . Activation of miR-31 function in already-established metastases elicits metastatic regression. Genes Dev 2011; 25: 646–659.

    Article  CAS  Google Scholar 

  12. Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 2008; 105: 3903–3908.

    Article  CAS  Google Scholar 

  13. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA 34 candidate tumor-suppressor genes. Curr Biol 2007; 17: 1298–1307.

    Article  CAS  Google Scholar 

  14. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26: 731–743.

    Article  CAS  Google Scholar 

  15. Xiong S, Zheng Y, Jiang P, Liu R, Liu X, Chu Y . MicroRNA-7 inhibits the growth of human non-small cell lung cancer A549 cells through targeting BCL-2. Int J Biol Sci 2011; 7: 805–814.

    Article  CAS  Google Scholar 

  16. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005; 65: 9628–9632.

    Article  CAS  Google Scholar 

  17. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006; 9: 189–198.

    Article  CAS  Google Scholar 

  18. Liu X, Sempere LF, Ouyang H, Memoli VA, Andrew AS, Luo Y et al. MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors. J Clin Invest 2010; 120: 1298–1309.

    Article  CAS  Google Scholar 

  19. Meng Z, Fu X, Chen X, Zeng S, Tian Y, Jove R et al. MiR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology 2010; 52: 2148–2157.

    Article  CAS  Google Scholar 

  20. Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 2010; 18: 367–381.

    Article  CAS  Google Scholar 

  21. Song Y, Zhao F, Wang Z, Liu Z, Chiang Y, Xu Y et al. Inverse association between miR-194 expression and tumor invasion in Gastric cancer. Ann Surg Oncol 2012; 19: S509–S517.

    Article  Google Scholar 

  22. Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer 2011; 10: 99–107.

    Article  CAS  Google Scholar 

  23. Aigner A . MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. J Mol Med 2011; 89: 445–457.

    Article  CAS  Google Scholar 

  24. Pan TL, Wang PW, Huang CC, Yeh CT, Hu TH, Yu JS . Network analysis and proteomic identification of vimentin as a key regulator associated with invasion and metastasis in human hepatocellular carcinoma cells. J Proteomics 2012; 75: 4676–4692.

    Article  CAS  Google Scholar 

  25. Wang JW, Peng SY, Li JT, Wang Y, Zhang ZP, Cheng Y et al. Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1. Cancer Lett 2009; 281: 71–81.

    Article  CAS  Google Scholar 

  26. Chadrick ED, John SI, Carolyn ER, Francis GS . Epithelial to mesenchymal transition: the doorway to metastasis in human lung cancers. J Thorac Cardiov Sur 2010; 140: 505–513.

    Article  Google Scholar 

  27. Wang JC, Su CC, Xu JB, Chen LZ, Hu XH, Wang GY et al. Novel microdeletion in the transforming growth factor β type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma. Gene Chromosome Canc 2007; 46: 192–201.

    Article  CAS  Google Scholar 

  28. Thiery JP . Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442–454.

    Article  CAS  Google Scholar 

  29. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 2007; 27: 91–105.

    Article  CAS  Google Scholar 

  30. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ et al. Combinatorial microRNA target predictions. Nat Genet 2005; 37: 495–500.

    Article  CAS  Google Scholar 

  31. Kruger J, Rehmsmeier M . RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res 2006; 34: W451–W454.

    Article  Google Scholar 

  32. Ge G, Greenspan DS . BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein. J Cell Biol 2006; 175: 111–120.

    Article  CAS  Google Scholar 

  33. Massague J . TGFβ in cancer. Cell 2008; 134: 215–230.

    Article  CAS  Google Scholar 

  34. Sehgal I, Thompson TC . Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-β 1 in human prostate cancer cell lines. Mol Biol Cell 1999; 10: 407–416.

    Article  CAS  Google Scholar 

  35. Sicinski P, Zacharek S, Kim C . Daulity of p27kip1 function in tumorigenesis. Gene Dev 2007; 21: 1703–1706.

    Article  CAS  Google Scholar 

  36. Besson A, Hwang HC, Cicero S, Donovan SL, Gurian-West M, Johnson D et al. Discovery of an oncogenic activity in p27kip1 that causes stem cell expression and a multiple tumor phenotype. Gene Dev 2007; 21: 1731–1746.

    Article  CAS  Google Scholar 

  37. Kawauchi T, Chihama K, Nabeshima Y, Hoshino M . Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol 2006; 8: 17–26.

    Article  CAS  Google Scholar 

  38. Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM . p27kip1 modulates cell migration through the regulation of RhoA activation. Gene Dev 2004; 18: 862–876.

    Article  CAS  Google Scholar 

  39. Ridley AJ, Hall A . The small GTP-binding protein rho regulates the assembly of focal adhensions and actin stress fibers in response to growth factors. Cell 1992; 70: 389–399.

    Article  CAS  Google Scholar 

  40. Krutzfeldt J, Rosch N, Hausser J, Manoharan M, Zavolan M, Stoffel M . MicroRNA-194 is a target of transcription factor 1 Tcf, HNF1α in adult liver and controls expression of frizzled-6. Hepatology 2012; 55: 98–107.

    Article  Google Scholar 

  41. Jenkins RH, Martin J, Phillips AO, Bowen T, Fraser D . Transforming growth factor beta-1 represses proximal tubular cell microRNA-192 expression via decreased Hepatocyte Nuclear Factor DNA binding. Biochem J 2012; 443: 407–416.

    Article  CAS  Google Scholar 

  42. Ebert MS, Neilson JR, Sharp PA . MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007; 4: 721–726.

    Article  CAS  Google Scholar 

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Acknowledgements

We owe gratefully to two anonymous reviewers whose constructively critical comments have been very helpful to improve the quality and presentation of an earlier version of the paper. We thank the unnamed patients for their consent to allow us to use the lung tissue samples in this research. This work was supported by the National Basic Research Program of China (2012CB316505) and National Natural Science Foundation of China (81172006). ZWL is also supported by the Leverhulme Trust (UK).

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Authors and Affiliations

  1. The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China

    X Wu, T Liu, O Fang, X Hu & Z Luo

  2. School of Biosciences, The University of Birmingham, Birmingham, UK

    L J Leach & Z Luo

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  1. X Wu
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Correspondence to X Hu or Z Luo.

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Wu, X., Liu, T., Fang, O. et al. miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1. Oncogene 33, 1506–1514 (2014). https://doi.org/10.1038/onc.2013.108

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