Slit/Robo信号与肿瘤
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摘要
神经导向因子Slit信号最早是在神经系统发现,并通过受体Robo家族成员发挥轴突导向排斥作用,近年来的研究表明其在包括肾脏、肺、皮肤等多种组织表达,参与调控正常的组织细胞生理功能,此外,在肿瘤中的研究表明Slit/Robo在肿瘤细胞的表达受到动态调控,从而参与多种肿瘤的发生发展过程。本文侧重于从Slit/Robo结构、Slit/Robo信号在肿瘤细胞中的表达,对肿瘤细胞恶变、增殖、迁移的作用,以及对肿瘤血管再生的影响等几个方面做一综述,探讨Slit/Robo信号的复杂性及其对不同肿瘤发生发展的作用,对其深入研究能够揭示Slit/Robo作为辅助诊断标志和肿瘤治疗靶点的潜在意义。
Slit acts as a neuronal guidance factor that plays an important role in guiding axon growth by repelling axons from the midline via Robo receptors.Furthermore,Slit is also expressed in many normal tissues and tumors.The role that Slit plays in tumor development is a topic of discussion.This article reviews its structure,its pattern of expression in tumors,and its role in tumor cell malignancy,cell proliferation,cell migration,and tumor angiogenesis.This article also discusses the complexity of its signaling pathways and its distinct roles in different tumors.This review seeks to provide new insight into the significance of Slit/Robo signaling as a potential diagnostic marker and therapeutic target for cancer therapy.
Slit acts as a neuronal guidance factor that plays an important role in guiding axon growth by repelling axons from the midline via Robo receptors.Furthermore,Slit is also expressed in many normal tissues and tumors.The role that Slit plays in tumor development is a topic of discussion.This article reviews its structure,its pattern of expression in tumors,and its role in tumor cell malignancy,cell proliferation,cell migration,and tumor angiogenesis.This article also discusses the complexity of its signaling pathways and its distinct roles in different tumors.This review seeks to provide new insight into the significance of Slit/Robo signaling as a potential diagnostic marker and therapeutic target for cancer therapy.
引文
[1]Niisslein-Volhard C,Wieschaus E,Kluding H,et al.Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster I.Zygotic loci on the second chromosome[J].Roux’s Arch Dev Biol,1984,193:267-82.
[2]Rothberg JM,Hartley DA,Walther Z,Artavanis-Tsakonas S,et al.Slit:an EGF-homologous locus of D.melanogaster involved in the development of the embryonic central nervous system[J].Cell,1988,55(6):1047-59.
[3]Hao JC,Yu TW,Fujisawa K,Culotti JG,et al.elegans slit acts in midline,dorsal-ventral,and anterior-posterior guidance via the SAX-3/Robo receptor[J].Neuron,2001,32(1):25-38.
[4]Li HS,Chen JH,Wu W,et al.Vertebrate slit,a secreted ligand for the transmembrane protein roundabout,is a repellent for olfactory bulb axons[J].Cell,1999,96(6):807-18.
[5]Yeo SY,Little MH,Yamada T,et al.Overexpression of a slit homologue impairs convergent extension of the mesoderm and causes cyclopia in embryonic zebrafish[J].Dev Biol,2001,230(1):1-17.
[6]Itoh A,Miyabayashi T,Ohno M,et al.Cloning and expressions of three mammalian homologues of Drosophila slit suggest possible roles for Slit in the formation and maintenance of the nervous system[J].Brain Res Mol Brain Res,1998,62(2):175-86.
[7]Kidd T,Brose K,Mitchell KJ,et al.Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evo2lutionarily conserved guidance receptors[J].Cell,1998,92:205-15.
[8]Kidd T,Bland KS,Goodman CS,et al.Slit is the midline repellent for the robo receptor in Drosophila[J].Cell,1999,96:785-94.
[9]Wu JY,Feng L,Park HT,et al.The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors[J].Nature,2001,410(6831):948-52.
[10]Kramer SG,Kidd T,Simpson JH,et al.Switching repulsion to attraction:changing responses to slit during transition in mesoderm migration[J].Science,2001,292(5517):737-40.
[11]Kaur S,Castellone MD,Bedell VM,et al.Robo4signaling in endothelial cells implies attraction guidance mechanisms[J].J Biol Chem,2006,281(16):11347-56.
[12]RE Dickinson,A Dallol,I Bieche,et al.Epigenetic inactivation of SLIT3and SLIT1genes in human cancers[J].British Journal of Cancer,2004,91(12):2071-8.
[13]Rothberg JM,Artavanis-Tsakonas S.Modularity of the slit protein.Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions[J].J Mol Biol,1992,227:367-70.
[14]Wang KH,Brose K,Arnott D,et al.Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching[J].Cell,1999,96:771-84.
[15]Sundaresan V,Roberts I,Bateman A,et al.The DUTT1gene,a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression[J].Mol Cell Neurosci,1998,11(1-2):29-35.
[16]Huminiecki L,GornM,Suchting S,et al.Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis[J].Genomics,2002,79(4):547-52.
[17]Cecile Morlot,Nicole M.Thielens,et al.Structural insights into the Slit-Robo complex[J].Proc Natl Acad Sci USA,2007,104(38):14923-8.
[18]Wang B,Xiao Y,Ding BB,et al.Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity[J].Cancer Cell,2003,4:19-29.
[19]Latil A,Chene L,Cochant-Priollet B,et al.quantification of expression of netrins slits and their receptors in human prostate tumors[J].Int J Cancer,2003,103:306-15.
[20]Mehmet EA,Ozlen K,Tamer Y,et al.Quantification of SLITROBO transcripts in hepatocellular carcinoma reveals two groups of genes with coordinate expression[J].BMC Cancer,2008,8:392.
[21]Zhou WJ,Zhen HG,Chi S,et al.Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis[J].Cell Research,2011,21:609-26.
[22]Kim GE,Lee KH,Choi YD,et al.Detection of Slit2promoter hypermethylation in tissue and serum samples from breast cancer patients[J].Virchows Arch,2011,459:383-90.
[23]Karin B,Albert D,Bosserhoff AK,et al.Slit-2facilitates interaction of P-cadherin with Robo-3and inhibits cell migration in an oral squamous cell carcinoma cell line[J].Carcinogenesis,2011,32(6):935-43.
[24]Jindan Yu,Qi Cao,Jianjun Yu,et al.The neuronal repellent SLIT2is a target for repression by EZH2in prostate cancer[J].Oncogene,2010,29(39):5370-80.
[25]Tseng RC,Lee SH,Hsu HS,et al.SLIT2attenuation during lung cancer prognosis deregulatesβ-Catenin and E-Cadherin and associates with poor prognosis[J].Cancer Res,2010,70:543-51.
[26]Jin J,You HY,Yu B,et al.Epigenetic inactivation of SLIT2in human hepatocellular carcinomas[J].Biochem Biophy Res Commun,2009,379:86-91.
[27]Kim HY,Zhang H,Li H,et al.Slit2inhibits tumor growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10:1411-20.
[28]Park KW,Morrison CM,Sorensen LK,et al.Robo4is a vascular-specific receptor that inhibits endothelial migration[J].Developmental Biol,2003,261:251-67.
[29]Gopeshwar N,Chandra G,Hugo AP,et al.Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression[J].Molecular Cancer,2006,5:16.
[30]Huang P,Kishida S,Cao DL,et al.The neuronal differentiation factor neuroD1downregulates the neuronal repellent factor Slit2expression and promotes cell motility and tumor formation of neuroblastoma[J].Cancer Res,2011,71(8):2938-48.
[31]Dana M,Brantley S,Charlene M,et al.Angiocrine factors modulate tumor proliferation and motility through EphA2repression of Slit2tumor suppressor function in endothelium[J].Cancer Res,2011,71(3):976-87.
[32]Marlow R,Strickland P,Lee JS,et al.SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4within breast epithelium[J].Cancer Res,2008,68(19):7819-27.
[33]Ashraf D,Dion M,Eamonn RM,et al.SLIT2axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells1[J].Cancer Res,2003,63:1054-8.
[34]Anil P,Aaron ZF,Yi R,et al.Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells[J].J Bioloficai Chem,2004,279:9115-24.
[35]Yiin JJ,Hu B,Michael JJ,et al.Slit2inhibits glioma cell invasion in the brain by suppression of Cdc42activity[J].Neuro Oncol,2009,11(6):779-89.
[36]Rebecca M,Mikhail B,Lise KS,et al.Vascular Robo4restricts proangiogenic VEGF signaling in breast[J].PNAS,2010,107(23):10520-5.
[37]Anil P,Aaron ZF,Yi R,et al.Robo4stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J].Nat Med,2008,14(4):448-53.
[38]Steven S,Paul H,Kiki T,et al.Soluble Robo4receptor inhibits in vivo angiogenesis and endothelial cell migration[J].Faseb J,2005,19(1):121-3.
[2]Rothberg JM,Hartley DA,Walther Z,Artavanis-Tsakonas S,et al.Slit:an EGF-homologous locus of D.melanogaster involved in the development of the embryonic central nervous system[J].Cell,1988,55(6):1047-59.
[3]Hao JC,Yu TW,Fujisawa K,Culotti JG,et al.elegans slit acts in midline,dorsal-ventral,and anterior-posterior guidance via the SAX-3/Robo receptor[J].Neuron,2001,32(1):25-38.
[4]Li HS,Chen JH,Wu W,et al.Vertebrate slit,a secreted ligand for the transmembrane protein roundabout,is a repellent for olfactory bulb axons[J].Cell,1999,96(6):807-18.
[5]Yeo SY,Little MH,Yamada T,et al.Overexpression of a slit homologue impairs convergent extension of the mesoderm and causes cyclopia in embryonic zebrafish[J].Dev Biol,2001,230(1):1-17.
[6]Itoh A,Miyabayashi T,Ohno M,et al.Cloning and expressions of three mammalian homologues of Drosophila slit suggest possible roles for Slit in the formation and maintenance of the nervous system[J].Brain Res Mol Brain Res,1998,62(2):175-86.
[7]Kidd T,Brose K,Mitchell KJ,et al.Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evo2lutionarily conserved guidance receptors[J].Cell,1998,92:205-15.
[8]Kidd T,Bland KS,Goodman CS,et al.Slit is the midline repellent for the robo receptor in Drosophila[J].Cell,1999,96:785-94.
[9]Wu JY,Feng L,Park HT,et al.The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors[J].Nature,2001,410(6831):948-52.
[10]Kramer SG,Kidd T,Simpson JH,et al.Switching repulsion to attraction:changing responses to slit during transition in mesoderm migration[J].Science,2001,292(5517):737-40.
[11]Kaur S,Castellone MD,Bedell VM,et al.Robo4signaling in endothelial cells implies attraction guidance mechanisms[J].J Biol Chem,2006,281(16):11347-56.
[12]RE Dickinson,A Dallol,I Bieche,et al.Epigenetic inactivation of SLIT3and SLIT1genes in human cancers[J].British Journal of Cancer,2004,91(12):2071-8.
[13]Rothberg JM,Artavanis-Tsakonas S.Modularity of the slit protein.Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions[J].J Mol Biol,1992,227:367-70.
[14]Wang KH,Brose K,Arnott D,et al.Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching[J].Cell,1999,96:771-84.
[15]Sundaresan V,Roberts I,Bateman A,et al.The DUTT1gene,a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression[J].Mol Cell Neurosci,1998,11(1-2):29-35.
[16]Huminiecki L,GornM,Suchting S,et al.Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis[J].Genomics,2002,79(4):547-52.
[17]Cecile Morlot,Nicole M.Thielens,et al.Structural insights into the Slit-Robo complex[J].Proc Natl Acad Sci USA,2007,104(38):14923-8.
[18]Wang B,Xiao Y,Ding BB,et al.Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity[J].Cancer Cell,2003,4:19-29.
[19]Latil A,Chene L,Cochant-Priollet B,et al.quantification of expression of netrins slits and their receptors in human prostate tumors[J].Int J Cancer,2003,103:306-15.
[20]Mehmet EA,Ozlen K,Tamer Y,et al.Quantification of SLITROBO transcripts in hepatocellular carcinoma reveals two groups of genes with coordinate expression[J].BMC Cancer,2008,8:392.
[21]Zhou WJ,Zhen HG,Chi S,et al.Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis[J].Cell Research,2011,21:609-26.
[22]Kim GE,Lee KH,Choi YD,et al.Detection of Slit2promoter hypermethylation in tissue and serum samples from breast cancer patients[J].Virchows Arch,2011,459:383-90.
[23]Karin B,Albert D,Bosserhoff AK,et al.Slit-2facilitates interaction of P-cadherin with Robo-3and inhibits cell migration in an oral squamous cell carcinoma cell line[J].Carcinogenesis,2011,32(6):935-43.
[24]Jindan Yu,Qi Cao,Jianjun Yu,et al.The neuronal repellent SLIT2is a target for repression by EZH2in prostate cancer[J].Oncogene,2010,29(39):5370-80.
[25]Tseng RC,Lee SH,Hsu HS,et al.SLIT2attenuation during lung cancer prognosis deregulatesβ-Catenin and E-Cadherin and associates with poor prognosis[J].Cancer Res,2010,70:543-51.
[26]Jin J,You HY,Yu B,et al.Epigenetic inactivation of SLIT2in human hepatocellular carcinomas[J].Biochem Biophy Res Commun,2009,379:86-91.
[27]Kim HY,Zhang H,Li H,et al.Slit2inhibits tumor growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10:1411-20.
[28]Park KW,Morrison CM,Sorensen LK,et al.Robo4is a vascular-specific receptor that inhibits endothelial migration[J].Developmental Biol,2003,261:251-67.
[29]Gopeshwar N,Chandra G,Hugo AP,et al.Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression[J].Molecular Cancer,2006,5:16.
[30]Huang P,Kishida S,Cao DL,et al.The neuronal differentiation factor neuroD1downregulates the neuronal repellent factor Slit2expression and promotes cell motility and tumor formation of neuroblastoma[J].Cancer Res,2011,71(8):2938-48.
[31]Dana M,Brantley S,Charlene M,et al.Angiocrine factors modulate tumor proliferation and motility through EphA2repression of Slit2tumor suppressor function in endothelium[J].Cancer Res,2011,71(3):976-87.
[32]Marlow R,Strickland P,Lee JS,et al.SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4within breast epithelium[J].Cancer Res,2008,68(19):7819-27.
[33]Ashraf D,Dion M,Eamonn RM,et al.SLIT2axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells1[J].Cancer Res,2003,63:1054-8.
[34]Anil P,Aaron ZF,Yi R,et al.Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells[J].J Bioloficai Chem,2004,279:9115-24.
[35]Yiin JJ,Hu B,Michael JJ,et al.Slit2inhibits glioma cell invasion in the brain by suppression of Cdc42activity[J].Neuro Oncol,2009,11(6):779-89.
[36]Rebecca M,Mikhail B,Lise KS,et al.Vascular Robo4restricts proangiogenic VEGF signaling in breast[J].PNAS,2010,107(23):10520-5.
[37]Anil P,Aaron ZF,Yi R,et al.Robo4stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J].Nat Med,2008,14(4):448-53.
[38]Steven S,Paul H,Kiki T,et al.Soluble Robo4receptor inhibits in vivo angiogenesis and endothelial cell migration[J].Faseb J,2005,19(1):121-3.