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PMID: 20300657 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor.

PLoS genetics ·Vol. 6 ·No. 3 ·2010-03-12 ·Pages e1000879

Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, Li Q, Qiao T, Zhao Q, Nie Y, Fan D

Abstract

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis.

MeSH Terms
3' Untranslated Regions/genetics Adult Aged Animals Base Sequence Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Humans Intercellular Signaling Peptides and Proteins/genetics,metabolism Lymphatic Metastasis/genetics,pathology Male Membrane Proteins/genetics,metabolism Mice MicroRNAs/genetics,metabolism Middle Aged Molecular Sequence Data Neoplasm Invasiveness Neoplasm Staging Nerve Tissue Proteins/genetics,metabolism Nucleic Acid Hybridization Prognosis Protein Binding Receptors, Immunologic/genetics,metabolism Reproducibility of Results Stomach Neoplasms/diagnosis,genetics,pathology
Chemicals
3' Untranslated Regions Intercellular Signaling Peptides and Proteins MIRN218 microRNA, human Membrane Proteins MicroRNAs Nerve Tissue Proteins Receptors, Immunologic SLIT3 protein, human roundabout protein Slit homolog 2 protein
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Tie Jun
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
Pan Yanglin
Zhao Lina
Wu Kaichun
Liu Jie
Sun Shiren
Guo Xuegang
Wang Biaoluo
Gang Yi
Zhang Yongguo
Li Quanjiang
Qiao Taidong
Zhao Qingchuan
Nie Yongzhan
Fan Daiming
Conflict of Interest

The authors have declared that no competing interests exist.

References (76)
76 references, click to expand
  1. MiR-92b and miR-9/9* are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors.
    Brain Pathol. 2009 Jul;19(3):375-83 PMID: 18624795
  2. Cancer. The metastasis cascade.
    Science. 2008 Sep 26;321(5897):1785-7 PMID: 18818347
  3. Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression.
    Oncology. 2005;69 Suppl 1:17-22 PMID: 16210872
  4. Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15062-6 PMID: 11734623
  5. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20350-5 PMID: 18077375
  6. Slit proteins: key regulators of axon guidance, axonal branching, and cell migration.
    Curr Opin Neurobiol. 2000 Feb;10(1):95-102 PMID: 10679444
  7. An intronic microRNA silences genes that are functionally antagonistic to its host gene.
    Nucleic Acids Res. 2008 Sep;36(16):5232-41 PMID: 18684991
  8. Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells.
    J Biol Chem. 2008 Sep 26;283(39):26624-33 PMID: 18611862
  9. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.
    Nature. 2007 Oct 11;449(7163):682-8 PMID: 17898713
  10. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines.
    Biochem Biophys Res Commun. 2008 Sep 5;373(4):607-12 PMID: 18602365
  11. MicroRNA signature predicts survival and relapse in lung cancer.
    Cancer Cell. 2008 Jan;13(1):48-57 PMID: 18167339
  12. Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice.
    Mech Dev. 2003 Sep;120(9):1059-70 PMID: 14550534
  13. Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune responses.
    J Immunol. 2003 Dec 15;171(12):6519-26 PMID: 14662852
  14. Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas.
    Biochem Biophys Res Commun. 2009 Jan 30;379(1):86-91 PMID: 19100240
  15. MicroRNAs--the micro steering wheel of tumour metastases.
    Nat Rev Cancer. 2009 Apr;9(4):293-302 PMID: 19262572
  16. Quantification of expression of netrins, slits and their receptors in human prostate tumors.
    Int J Cancer. 2003 Jan 20;103(3):306-15 PMID: 12471613
  17. A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer.
    PLoS One. 2009;4(1):e4171 PMID: 19137069
  18. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins.
    Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5874-8 PMID: 18390668
  19. Deletions in chromosome 4 differentially associated with the development of cervical cancer: evidence of slit2 as a candidate tumor suppressor gene.
    Hum Genet. 2007 Aug;122(1):71-81 PMID: 17609981
  20. Regulation of axon guidance by slit and netrin signaling in the Drosophila ventral nerve cord.
    Genetics. 2007 Aug;176(4):2235-46 PMID: 17565966
  21. Differential expression of the LGI and SLIT families of genes in human cancer cells.
    Gene. 2005 Aug 15;356:85-90 PMID: 16000246
  22. Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis.
    Cancer Res. 2009 Feb 15;69(4):1279-83 PMID: 19190326
  23. The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple aspects of axon guidance in C. elegans.
    Cell. 1998 Jan 23;92(2):217-27 PMID: 9458046
  24. Intronic microRNA (miRNA).
    J Biomed Biotechnol. 2006;2006(4):26818 PMID: 17057362
  25. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis.
    Cancer Cell. 2006 Mar;9(3):189-98 PMID: 16530703
  26. Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain.
    Development. 2006 Jun;133(11):2243-52 PMID: 16690755
  27. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.
    Cell Res. 2008 Mar;18(3):350-9 PMID: 18270520
  28. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.
    Cancer Cell. 2008 Mar;13(3):272-86 PMID: 18328430
  29. Transcriptional network governing the angiogenic switch in human pancreatic cancer.
    Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12890-5 PMID: 17652168
  30. Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis.
    Urol Oncol. 2011 May-Jun;29(3):265-9 PMID: 19372056
  31. Suppression of cell growth and invasion by miR-205 in breast cancer.
    Cell Res. 2009 Apr;19(4):439-48 PMID: 19238171
  32. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer.
    Prostate. 2008 Aug 1;68(11):1152-64 PMID: 18459106
  33. Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: potential role of MIF in gastric carcinogenesis.
    Gut. 2006 Jun;55(6):797-802 PMID: 16488898
  34. A microRNA expression signature of human solid tumors defines cancer gene targets.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 PMID: 16461460
  35. Oncomirs - microRNAs with a role in cancer.
    Nat Rev Cancer. 2006 Apr;6(4):259-69 PMID: 16557279
  36. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors.
    Nature. 2001 Apr 19;410(6831):948-52 PMID: 11309622
  37. Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation.
    Nat Genet. 2002 Apr;30(4):363-4 PMID: 11896390
  38. The diverse functions of microRNAs in animal development and disease.
    Dev Cell. 2006 Oct;11(4):441-50 PMID: 17011485
  39. Slits and Roundabouts in cancer, tumour angiogenesis and endothelial cell migration.
    Angiogenesis. 2008;11(1):13-21 PMID: 18264786
  40. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer.
    Oncogene. 2008 Apr 3;27(15):2128-36 PMID: 17968323
  41. Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration.
    FASEB J. 2005 Jan;19(1):121-3 PMID: 15486058
  42. Amplicons on chromosome 3 contain oncogenes induced by recurrent exposure to 12-O-tetradecanoylphorbol-13-acetate and sodium n-butyrate and Epstein-Barr virus reactivation in a nasopharyngeal carcinoma cell line.
    Cancer Genet Cytogenet. 2008 Aug;185(1):1-10 PMID: 18656687
  43. Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer.
    Oncol Rep. 2006 Jun;15(6):1437-43 PMID: 16685377
  44. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31.
    Int J Cancer. 2009 May 1;124(9):2236-42 PMID: 19127597
  45. Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma.
    Neoplasia. 2008 Dec;10(12):1411-20 PMID: 19048120
  46. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells.
    Biochem Biophys Res Commun. 2009 Jun 5;383(3):280-5 PMID: 19302977
  47. Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells.
    Oncogene. 2008 Apr 17;27(18):2575-82 PMID: 17998940
  48. Slit2 involvement in glioma cell migration is mediated by Robo1 receptor.
    J Neurooncol. 2008 Mar;87(1):1-7 PMID: 17968499
  49. Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1.
    Cancer Res. 2007 May 15;67(10):4816-26 PMID: 17510411
  50. Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis.
    Oncogene. 2008 Jul 24;27(32):4488-96 PMID: 18372914
  51. The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells.
    Breast Cancer Res Treat. 2007 Dec;106(3):333-42 PMID: 17268810
  52. Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis.
    Genomics. 2002 Apr;79(4):547-52 PMID: 11944987
  53. Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target.
    Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3257-64 PMID: 16740745
  54. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor.
    Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1814-9 PMID: 19188590
  55. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity.
    Cancer Cell. 2003 Jul;4(1):19-29 PMID: 12892710
  56. MicroRNA expression profiles classify human cancers.
    Nature. 2005 Jun 9;435(7043):834-8 PMID: 15944708
  57. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma.
    Cancer Res. 2007 Jul 1;67(13):6092-9 PMID: 17616664
  58. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
    Cell. 2005 Jan 14;120(1):15-20 PMID: 15652477
  59. Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression.
    Mol Cancer. 2006 May 15;5:16 PMID: 16700909
  60. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line.
    Am J Respir Cell Mol Biol. 1997 Sep;17(3):353-60 PMID: 9308922
  61. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors.
    Cell. 1998 Jan 23;92(2):205-15 PMID: 9458045
  62. MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma.
    Clin Cancer Res. 2009 Mar 15;15(6):1915-22 PMID: 19276261
  63. Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells.
    J Leukoc Biol. 2007 Sep;82(3):465-76 PMID: 17565045
  64. Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers.
    Oncogene. 2002 May 2;21(19):3020-8 PMID: 12082532
  65. Cancerous miRNAs and their regulation.
    Cell Cycle. 2008 Jun 1;7(11):1529-38 PMID: 18469525
  66. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis.
    Nat Cell Biol. 2008 Feb;10(2):202-10 PMID: 18193036
  67. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1.
    Nat Cell Biol. 2008 May;10(5):593-601 PMID: 18376396
  68. Magic roundabout, a tumor endothelial marker: expression and signaling.
    Biochem Biophys Res Commun. 2005 Jul 1;332(2):533-41 PMID: 15894287
  69. Endogenous human microRNAs that suppress breast cancer metastasis.
    Nature. 2008 Jan 10;451(7175):147-52 PMID: 18185580
  70. Tumor metastasis: mechanistic insights and clinical challenges.
    Nat Med. 2006 Aug;12(8):895-904 PMID: 16892035
  71. Regulation of commissural axon pathfinding by slit and its Robo receptors.
    Annu Rev Cell Dev Biol. 2006;22:651-75 PMID: 17029581
  72. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis.
    EMBO Rep. 2009 Apr;10(4):400-5 PMID: 19247375
  73. Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma.
    Oncogene. 2008 Apr 3;27(15):2137-47 PMID: 17952116
  74. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells.
    Cancer Lett. 2009 Mar 8;275(1):44-53 PMID: 19006648
  75. MicroRNAs and the hallmarks of cancer.
    Oncogene. 2006 Oct 9;25(46):6170-5 PMID: 17028596
  76. Cancer metastasis: building a framework.
    Cell. 2006 Nov 17;127(4):679-95 PMID: 17110329
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000879
Published
2010-03-12
Epub
2010-00-12
Pages
e1000879
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2837402
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.1000879 PMC Full Text View journal details
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