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MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1

Oncogene volume 32, pages 4294–4303 (2013)Cite this article

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Abstract

MicroRNAs have key roles in tumor metastasis. Here, we describe the regulation and function of miR-34a and miR-34c (miR-34a/c) in breast cancer metastasis. Expression analysis verified that miR-34a/c expression is significantly decreased in metastatic breast cancer cells and human primary breast tumors with lymph node metastases. Overexpression of miR-34a/c could inhibit breast cancer cell migration and invasion in vitro and distal pulmonary metastasis in vivo. Further studies revealed that Fos-related antigen 1 (Fra-1 or Fosl1) is a downstream target of miR-34a/c as miR-34a/c bound directly to the 3′untranslated region of Fra-1, subsequently reducing both the mRNA and protein levels of Fra-1. Silencing of Fra-1 recapitulated the effects of miR-34a/c overexpression, whereas enforced expression of Fra-1 reverses the suppressive effects of miR-34a/c. Moreover, significant downregulation of miR-34a in metastatic breast cancer tissues was found to be inversely correlated with Fra-1 expression. Our results demonstrate that miR-34a/c functions as a metastasis suppressor to regulate breast cancer migration and invasion through targeting Fra-1 oncogene and suggest a therapeutic application of miR-34 in breast cancer.

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References

  1. Chaffer CL, Weinberg RA . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Steeg PS . Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12: 895–904.

    Article  CAS  Google Scholar 

  4. Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA . MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer 2009; 9: 293–302.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. 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: 1032–1046.

    Article  CAS  Google Scholar 

  7. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008; 451: 147–152.

    Article  CAS  Google Scholar 

  8. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 2008; 68: 7846–7854.

    Article  CAS  Google Scholar 

  9. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10: 593–601.

    Article  CAS  Google Scholar 

  10. Lv XB, Jiao Y, Qing Y, Hu H, Cui X, Lin T et al. miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro. Chin J Cancer 2011; 30: 821–830.

    Article  Google Scholar 

  11. Wu ZS, Wu Q, Wang CQ, Wang XN, Huang J, Zhao JJ et al. miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer 2011; 117: 2842–2852.

    Article  CAS  Google Scholar 

  12. Li Y, Zhang M, Chen H, Dong Z, Ganapathy V, Thangaraju M et al. Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis. Cancer Res 2010; 70: 7894–7904.

    Article  CAS  Google Scholar 

  13. Ma L, Teruya-Feldstein J, Weinberg RA . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449: 682–688.

    Article  CAS  Google Scholar 

  14. Gee HE, Camps C, Buffa FM, Colella S, Sheldon H, Gleadle JM et al. MicroRNA-10b and breast cancer metastasis. Nature 2008; 455: E8–E9.

    Article  CAS  Google Scholar 

  15. Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O’Brien C et al. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal 2011; 4: ra41.

    Article  Google Scholar 

  16. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26: 745–752.

    CAS  Google Scholar 

  17. 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 

  18. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 2007; 17: 1298–1307.

    Article  CAS  Google Scholar 

  19. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H . Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA 2007; 104: 15472–15477.

    Article  CAS  Google Scholar 

  20. Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R et al. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett 2008; 582: 1564–1568.

    Article  CAS  Google Scholar 

  21. Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 2009; 275: 44–53.

    Article  CAS  Google Scholar 

  22. Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol 2011; 195: 417–433.

    Article  CAS  Google Scholar 

  23. Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y et al. Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res 2008; 68: 4123–4132.

    Article  CAS  Google Scholar 

  24. Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D et al. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 2010; 9: 1031–1036.

    Article  CAS  Google Scholar 

  25. Welch C, Chen Y, Stallings RL . MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007; 26: 5017–5022.

    Article  CAS  Google Scholar 

  26. Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P et al. The MYCN oncogene is a direct target of miR-34a. Oncogene 2008; 27: 5204–5213.

    Article  CAS  Google Scholar 

  27. Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4: e6816.

    Article  Google Scholar 

  28. Chim CS, Wong KY, Qi Y, Loong F, Lam WL, Wong LG et al. Epigenetic inactivation of the miR-34a in hematological malignancies. Carcinogenesis 2010; 31: 745–750.

    Article  CAS  Google Scholar 

  29. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 2010; 70: 5923–5930.

    Article  CAS  Google Scholar 

  30. Cannell IG, Kong YW, Johnston SJ, Chen ML, Collins HM, Dobbyn HC et al. p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. Proc Natl Acad Sci USA 2010; 107: 5375–5380.

    Article  CAS  Google Scholar 

  31. Chen L, Mayer JA, Krisko TI, Speers CW, Wang T, Hilsenbeck SG et al. Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Res 2009; 69: 8853–8861.

    Article  CAS  Google Scholar 

  32. Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M et al. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 2010; 17: 236–245.

    Article  CAS  Google Scholar 

  33. Huang da W, Sherman BT, Lempicki RA . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37: 1–13.

    Article  Google Scholar 

  34. Hermeking H . The miR-34 family in cancer and apoptosis. Cell Death Differ 2010; 17: 193–199.

    Article  CAS  Google Scholar 

  35. Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E et al. Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol Cell Biol 1998; 18: 7095–7105.

    Article  CAS  Google Scholar 

  36. Ramos-Nino ME, Scapoli L, Martinelli M, Land S, Mossman BT . Microarray analysis and RNA silencing link fra-1 to cd44 and c-met expression in mesothelioma. Cancer Res 2003; 63: 3539–3545.

    CAS  Google Scholar 

  37. Debinski W, Gibo DM . Fos-related antigen 1 modulates malignant features of glioma cells. Mol Cancer Res 2005; 3: 237–249.

    CAS  Google Scholar 

  38. Tkach V, Tulchinsky E, Lukanidin E, Vinson C, Bock E, Berezin V . Role of the Fos family members, c-Fos, Fra-1 and Fra-2, in the regulation of cell motility. Oncogene 2003; 22: 5045–5054.

    Article  CAS  Google Scholar 

  39. Usui A, Hoshino I, Akutsu Y, Sakata H, Nishimori T, Murakami K et al. The molecular role of Fra-1 and its prognostic significance in human esophageal squamous cell carcinoma. Cancer 2012; 118: 3387–3396.

    Article  CAS  Google Scholar 

  40. Sayan AE, Stanford R, Vickery R, Grigorenko E, Diesch J, Kulbicki K et al. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 2011; 25: 8.

    Google Scholar 

  41. Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 2001; 61: 5168–5178.

    CAS  Google Scholar 

  42. Belguise K, Kersual N, Galtier F, Chalbos D . FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene 2005; 24: 1434–1444.

    Article  CAS  Google Scholar 

  43. Luo YP, Zhou H, Krueger J, Kaplan C, Liao D, Markowitz D et al. The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. Oncogene 2010; 29: 662–673.

    Article  CAS  Google Scholar 

  44. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999–3004.

    Article  CAS  Google Scholar 

  45. Osborne RJ, Hamshere MG . A genome-wide map showing common regions of loss of heterozygosity/allelic imbalance in breast cancer. Cancer Res 2000; 60: 3706–3712.

    CAS  Google Scholar 

  46. Bieche I, Khodja A, Lidereau R . Deletion mapping of chromosomal region 1p32-pter in primary breast cancer. Genes Chromosomes Cancer 1999; 24: 255–263.

    Article  CAS  Google Scholar 

  47. Nagai H, Negrini M, Carter SL, Gillum DR, Rosenberg AL, Schwartz GF et al. Detection and cloning of a common region of loss of heterozygosity at chromosome 1p in breast cancer. Cancer Res 1995; 55: 1752–1757.

    CAS  Google Scholar 

  48. Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD . High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomarkers Prev 2003; 12: 915–919.

    CAS  Google Scholar 

  49. Ellsworth RE, Hooke JA, Love B, Kane JL, Patney HL, Ellsworth DL et al. Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors. Breast Cancer Res Treat 2008; 107: 259–265.

    Article  Google Scholar 

  50. Winqvist R, Hampton GM, Mannermaa A, Blanco G, Alavaikko M, Kiviniemi H et al. Loss of heterozygosity for chromosome 11 in primary human breast tumors is associated with poor survival after metastasis. Cancer Res 1995; 55: 2660–2664.

    CAS  Google Scholar 

  51. Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D et al. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA 2008; 105: 13556–13561.

    Article  CAS  Google Scholar 

  52. Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008; 7: 2591–2600.

    Article  CAS  Google Scholar 

  53. Yu F, Jiao Y, Zhu Y, Wang Y, Zhu J, Cui X et al. MiR-34c down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells. J Biol Chem 2012; 287: 465–473.

    Article  CAS  Google Scholar 

  54. Siemens H, Jackstadt R, Hunten S, Kaller M, Menssen A, Gotz U et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 2011; 10: 4256–4271.

    Article  CAS  Google Scholar 

  55. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17: 211–215.

    Article  CAS  Google Scholar 

  56. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 2011; 13: 1353–1360.

    Article  CAS  Google Scholar 

  57. Migliore C, Petrelli A, Ghiso E, Corso S, Capparuccia L, Eramo A et al. MicroRNAs impair MET-mediated invasive growth. Cancer Res 2008; 68: 10128–10136.

    Article  CAS  Google Scholar 

  58. Hwang CI, Matoso A, Corney DC, Flesken-Nikitin A, Korner S, Wang W et al. Wild-type p53 controls cell motility and invasion by dual regulation of MET expression. Proc Natl Acad Sci USA 2011; 108: 14240–14245.

    Article  CAS  Google Scholar 

  59. Mudduluru G, Ceppi P, Kumarswamy R, Scagliotti GV, Papotti M, Allgayer H . Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene 2011; 30: 2888–2899.

    Article  CAS  Google Scholar 

  60. Mackiewicz M, Huppi K, Pitt JJ, Dorsey TH, Ambs S, Caplen NJ . Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. Breast Cancer Res Treat 2011; 130: 663–679.

    Article  CAS  Google Scholar 

  61. Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial--mesenchymal transition. J Cell Biol 2011; 195: 417–433.

    Article  CAS  Google Scholar 

  62. Wu J, Wu G, Lv L, Ren YF, Zhang XJ, Xue YF et al. MicroRNA-34a inhibits migration and invasion of colon cancer cells via targeting to Fra-1. Carcinogenesis 2012; 33: 519–528.

    Article  CAS  Google Scholar 

  63. Serewko MM, Popa C, Dahler AL, Smith L, Strutton GM, Coman W et al. Alterations in gene expression and activity during squamous cell carcinoma development. Cancer Res 2002; 62: 3759–3765.

    CAS  Google Scholar 

  64. Chiappetta G, Tallini G, De Biasio MC, Pentimalli F, de Nigris F, Losito S et al. FRA-1 expression in hyperplastic and neoplastic thyroid diseases. Clin Cancer Res 2000; 6: 4300–4306.

    CAS  Google Scholar 

  65. Milde-Langosch K, Roder H, Andritzky B, Aslan B, Hemminger G, Brinkmann A et al. The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast Cancer Res Treat 2004; 86: 139–152.

    Article  CAS  Google Scholar 

  66. Bamberger AM, Methner C, Lisboa BW, Stadtler C, Schulte HM, Loning T et al. Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive tumor phenotype. Int J Cancer 1999; 84: 533–538.

    Article  CAS  Google Scholar 

  67. Vial E, Marshall CJ . Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. J Cell Sci 2003; 116 (Pt 24): 4957–4963.

    Article  CAS  Google Scholar 

  68. Tian Y, Luo A, Cai Y, Su Q, Ding F, Chen H et al. MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J Biol Chem 2010; 285: 7986–7994.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ziqiang Zhang, Yongquan Wang and Zhiyuan Wu for providing technical support. This work was supported by the National Basic Research Program of China (2011CB504205) and National Natural Science Foundation of China (91019009, 81021061).

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  1. State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    S Yang, Y Li, T Zhang, S Li, A Luo, H Chen, F Ding & Z Liu

  2. Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    J Gao & X Wang

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Yang, S., Li, Y., Gao, J. et al. MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 32, 4294–4303 (2013). https://doi.org/10.1038/onc.2012.432

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