#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor


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.


Vyšlo v časopise: MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor. PLoS Genet 6(3): e32767. doi:10.1371/journal.pgen.1000879
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000879

Souhrn

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.


Zdroje

1. OueN

AungPP

MitaniY

KuniyasuH

NakayamaH

2005 Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression. Oncology 69 Suppl 1 17 22

2. GuptaGP

MassagueJ

2006 Cancer metastasis: building a framework. Cell 127 679 695

3. KleinCA

2008 Cancer. The metastasis cascade. Science 321 1785 1787

4. SteegPS

2006 Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12 895 904

5. NicolosoMS

SpizzoR

ShimizuM

RossiS

CalinGA

2009 MicroRNAs - the micro steering wheel of tumour metastases Nat Rev Cancer

6. MaL

Teruya-FeldsteinJ

WeinbergRA

2007 Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449 682 688

7. HuangQ

GumireddyK

SchrierM

le SageC

NagelR

2008 The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10 202 210

8. LeeDY

DengZ

WangCH

YangBB

2007 MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci U S A 104 20350 20355

9. GregoryPA

BertAG

PatersonEL

BarrySC

TsykinA

2008 The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10 593 601

10. WuH

ZhuS

MoYY

2009 Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Res

11. HurstDR

EdmondsMD

ScottGK

BenzCC

VaidyaKS

2009 Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res 69 1279 1283

12. PrueittRL

YiM

HudsonRS

WallaceTA

HoweTM

2008 Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate 68 1152 1164

13. LiT

LiD

ShaJ

SunP

HuangY

2009 MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun

14. SenguptaS

den BoonJA

ChenIH

NewtonMA

StanhopeSA

2008 MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A 105 5874 5878

15. VeerlaS

LindgrenD

KvistA

FrigyesiA

StaafJ

2009 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 124 2236 2242

16. SeguraMF

HannifordD

MenendezS

ReavieL

ZouX

2009 Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci U S A 106 1814 1819

17. NassD

RosenwaldS

MeiriE

GiladS

Tabibian-KeissarH

2008 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

18. AsanganiIA

RasheedSA

NikolovaDA

LeupoldJH

ColburnNH

2008 MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27 2128 2136

19. LewisBP

BurgeCB

BartelDP

2005 Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120 15 20

20. LaiEC

2002 Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 30 363 364

21. KloostermanWP

PlasterkRH

2006 The diverse functions of microRNAs in animal development and disease. Dev Cell 11 441 450

22. Esquela-KerscherA

SlackFJ

2006 Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6 259 269

23. LuJ

GetzG

MiskaEA

Alvarez-SaavedraE

LambJ

2005 MicroRNA expression profiles classify human cancers. Nature 435 834 838

24. VoliniaS

CalinGA

LiuCG

AmbsS

CimminoA

2006 A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 103 2257 2261

25. MartinezI

GardinerAS

BoardKF

MonzonFA

EdwardsRP

2008 Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene 27 2575 2582

26. PetroccaF

VisoneR

OnelliMR

ShahMH

NicolosoMS

2008 E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13 272 286

27. YanaiharaN

CaplenN

BowmanE

SeikeM

KumamotoK

2006 Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9 189 198

28. LeiteKR

Sousa-CanavezJM

ReisST

TomiyamaAH

Camara-LopesLH

2009 Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis. Urol Oncol

29. HeXX

YangJ

DingYW

LiuW

ShenQY

2006 Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: potential role of MIF in gastric carcinogenesis. Gut 55 797 802

30. WangB

XiaoY

DingB-B

ZhangN

YuanX-b

2003 Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4 19 29

31. SuchtingS

HealP

TahtisK

StewartLM

BicknellR

2005 Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J 19 121 123

32. GroneJ

DoeblerO

LoddenkemperC

HotzB

BuhrHJ

2006 Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer. Oncol Rep 15 1437 1443

33. ItoH

FunahashiS

YamauchiN

ShibaharaJ

MidorikawaY

2006 Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target. Clin Cancer Res 12 3257 3264

34. LeeCH

FangCY

SheuJJ

ChangY

TakadaK

2008 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 185 1 10

35. LeggJA

HerbertJM

ClissoldP

BicknellR

2008 Slits and Roundabouts in cancer, tumour angiogenesis and endothelial cell migration. Angiogenesis 11 13 21

36. MertschS

SchmitzN

JeibmannA

GengJG

PaulusW

2008 Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. J Neurooncol 87 1 7

37. SchmidBC

RezniczekGA

FabjaniG

YonedaT

LeodolterS

2007 The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells. Breast Cancer Res Treat 106 333 342

38. GramantieriL

FerracinM

FornariF

VeroneseA

SabbioniS

2007 Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67 6092 6099

39. SethP

LinY

HanaiJ

ShivalingappaV

DuyaoMP

2005 Magic roundabout, a tumor endothelial marker: expression and signaling. Biochem Biophys Res Commun 332 533 541

40. AbdollahiA

SchwagerC

KleeffJ

EspositoI

DomhanS

2007 Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci U S A 104 12890 12895

41. ShiXB

TepperCG

WRW

2008 Cancerous miRNAs and their regulation. Cell Cycle 7 1529 1538

42. LinSL

MillerJD

YingSY

2006 Intronic MicroRNA (miRNA). J Biomed Biotechnol 2006: 26818. 26818

43. ChuYW

YangPC

YangSC

ShyuYC

HendrixMJ

1997 Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 17 353 360

44. WangCC

TsaiMF

DaiTH

HongTM

ChanWK

2007 Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res 67 4816 4826

45. TsengRC

LinRK

WenCK

TsengC

HsuHS

2008 Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis. Oncogene 27 4488 4496

46. ChangDK

LinCT

WuCH

WuHC

2009 A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer. PLoS ONE 4 e4171 doi:10.1371/journal.pone.0004171

47. TorngPL

LeeYC

HuangCY

YeJH

LinYS

2008 Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma. Oncogene 27 2137 2147

48. YuSL

ChenHY

ChangGC

ChenCY

ChenHW

2008 MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13 48 57

49. ZhuS

WuH

WuF

NieD

ShengS

2008 MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18 350 359

50. HiyoshiY

KamoharaH

KarashimaR

SatoN

ImamuraY

2009 MicroRNA-21 Regulates the Proliferation and Invasion in Esophageal Squamous Cell Carcinoma. Clin Cancer Res

51. CrawfordM

BrawnerE

BatteK

YuL

HunterMG

2008 MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun 373 607 612

52. TavazoieSF

AlarconC

OskarssonT

PaduaD

WangQ

2008 Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451 147 152

53. LiN

FuH

TieY

HuZ

KongW

2009 miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 275 44 53

54. GebeshuberCA

ZatloukalK

MartinezJ

2009 miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep

55. DalmayT

EdwardsDR

2006 MicroRNAs and the hallmarks of cancer. Oncogene 25 6170 6175

56. HuminieckiL

GornM

SuchtingS

PoulsomR

BicknellR

2002 Magic Roundabout Is a New Member of the Roundabout Receptor Family That Is Endothelial Specific and Expressed at Sites of Active Angiogenesis. Genomics 79 547 552

57. BroseK

Tessier-LavigneM

2000 Slit proteins: key regulators of axon guidance, axonal branching, and cell migration. Curr Opin Neurobiol 10 95 102

58. KiddT

BroseK

MitchellKJ

FetterRD

Tessier-LavigneM

1998 Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92 205 215

59. ZallenJA

YiBA

BargmannCI

1998 The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple aspects of axon guidance in C. elegans. Cell 92 217 227

60. DicksonBJ

GilestroGF

2006 Regulation of commissural axon pathfinding by slit and its Robo receptors. Annu Rev Cell Dev Biol 22 651 675

61. BhatKM

GaziovaI

KrishnanS

2007 Regulation of axon guidance by slit and netrin signaling in the Drosophila ventral nerve cord. Genetics 176 2235 2246

62. WuJY

FengL

ParkHT

HavliogluN

WenL

2001 The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410 948 952

63. GuanH

ZuG

XieY

TangH

JohnsonM

2003 Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune responses. J Immunol 171 6519 6526

64. PrasadA

QamriZ

WuJ

GanjuRK

2007 Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells. J Leukoc Biol 82 465 476

65. RossiMR

HuntoonK

CowellJK

2005 Differential expression of the LGI and SLIT families of genes in human cancer cells. Gene 356 85 90

66. NarayanG

GoparajuC

Arias-PulidoH

KaufmannAM

SchneiderA

2006 Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression. Mol Cancer 5 16

67. SinghRK

IndraD

MitraS

MondalRK

BasuPS

2007 Deletions in chromosome 4 differentially associated with the development of cervical cancer: evidence of slit2 as a candidate tumor suppressor gene. Hum Genet 122 71 81

68. PrasadA

ParuchuriV

PreetA

LatifF

GanjuRK

2008 Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells. J Biol Chem 283 26624 26633

69. DallolA

ForgacsE

MartinezA

SekidoY

WalkerR

2002 Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers. Oncogene 21 3020 3028

70. XianJ

ClarkKJ

FordhamR

PannellR

RabbittsTH

2001 Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene. Proc Natl Acad Sci U S A 98 15062 15066

71. LatilA

CheneL

Cochant-PriolletB

ManginP

FournierG

2003 Quantification of expression of netrins, slits and their receptors in human prostate tumors. Int J Cancer 103 306 315

72. KimHK

ZhangH

LiH

WuTT

SwisherS

2008 Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma. Neoplasia 10 1411 1420

73. JinJ

YouH

YuB

DengY

TangN

2009 Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas. Biochem Biophys Res Commun 379 86 91

74. AndrewsW

LiapiA

PlachezC

CamurriL

ZhangJ

2006 Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development 133 2243 2252

75. LiuJ

ZhangL

WangD

ShenH

JiangM

2003 Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice. Mech Dev 120 1059 1070

76. BarikS

2008 An intronic microRNA silences genes that are functionally antagonistic to its host gene. Nucleic Acids Res 36 5232 5241

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2010 Číslo 3
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#