Slit/Robo信号通路在妇科肿瘤发生中的作用
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摘要
Slit/Robo信号作为神经导向因子在神经系统发育中具有导向轴突生长和排斥神经细胞迁移的重要作用。目前研究发现,Slit/Robo信号也可能参与了肿瘤发生发展中某些关键步骤,如细胞迁移和肿瘤新生血管的形成,但其在妇科肿瘤中的作用尚不清楚。从Slit/Robo信号在女性生殖系统生理、病理状态下的表达情况,以及参与妇科肿瘤发生的机制等方面做一综述。
As important axon guidance molecules,the Slit family of secreted proteins acts through the Roundabout(Robo) receptors to direct axonal growth and repel axonal migration during central nervous system development.Recent research has revealed that the Slit/Robo pathway might play roles in some pivotal processes in tumorigenesis,such as cell migration and tumor angiogenesis.However,the role of Slit/Robo in gynecological tumorigenesis remains largely unknown.This review will examine the roles of this pathway in the physiology and pathology of the reproductive system and highlight areas for future research.
As important axon guidance molecules,the Slit family of secreted proteins acts through the Roundabout(Robo) receptors to direct axonal growth and repel axonal migration during central nervous system development.Recent research has revealed that the Slit/Robo pathway might play roles in some pivotal processes in tumorigenesis,such as cell migration and tumor angiogenesis.However,the role of Slit/Robo in gynecological tumorigenesis remains largely unknown.This review will examine the roles of this pathway in the physiology and pathology of the reproductive system and highlight areas for future research.
引文
Braisted JE,Ringstedt T,O′Leary DD.Slits are chemorepellents endogenous to hypothalamus and steer thalamocortical axons into ventral telencephalon[J].Cereb Cortex,2009,19(Suppl 1):144-151.
Sasaki T,Komatsu Y,Watakabe A,et al.Prefrontal-enriched SLIT1 expression in Old World monkey cortex established during the postnatal development[J].Cereb Cortex,2010,20(10):2496-2510.
Ye BQ,Geng ZH,Ma L,et al.Slit2regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation[J].J Immunol,2010,185(10):6294-6305.
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(1):19-29.
London NR,Li DY.Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm[J].Curr Opin Hematol,2011,18(3):186-190.
Dickinson RE,Duncan WC.The SLIT-ROBO pathway:a regulator of cell function with implications for the reproductive system[J].Reproduction,2010,139(4):697-704.
Duncan WC,McDonald SE,Dickinson RE,et al.Expression of the repulsive SLIT/ROBO pathway in the human endometrium and Fallopian tube[J].Mol Hum Reprod,2010,16(12):950-959.
Ma S,Liu X,Geng JG,et al.Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma[J].Am J Obstet Gynecol,2010,202(1):68.e1-68.e11.
Narayan G,Goparaju C,Arias-Pulido H,et al.Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression[J].Mol Cancer,2006,5:16.
Qiu H,Zhu J,Yu J,et al.SLIT2 is epigenetically silenced in ovarian cancers and suppresses growth when activated[J].Asian Pac J Cancer Prev,2011,12(3):791-795.
Dickinson RE,Fegan KS,Ren X,et al.Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells[J].PLoS One,2011,6(11):e27792.
Latil A,Chene L,Cochant-Priollet B,et al.Quantification of expression of netrins,slits and their receptors in human prostate tumors[J].In J Cancer,2003,103(3):306-315.
Bacon C,Endris V,Rappold G.Dynamic expression of the Slit-Robo GTPase activating protein genes during development of the murine nervous system[J].J Comp Neurol,2009,513(2):224-236.
Bauer K,Dowejko A,Bosserhoff AK,et al.Slit-2facilitates interaction of P-cadherin with Robo-3and inhibits cell mig ration in an oral squamous cell carcinoma cell line[J].Carcinogenesis,2011,32(6):935-943.
Stella MC,Trusolino L,Comoglio PM.The Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis[J].Mol Biol Cell,2009,20(2):642-657.
Donninger H,Bonome T,Radonovich M,et al.Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways[J].Oncogene,2004,23(49):8065-8077.
Kim HK,Zhang H,Li H,et al.Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10(12):1411-1420.
Schmid BC,Rezniczek GA,Fabjani G,et al.The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells[J].Breast Cancer Res Treat,2007,106(3):333-342.
Zhou WJ,Geng ZH,Chi S,et al.Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis[J].Cell Res,2011,21(4):609-626.
Liao WX,Wing DA,Geng JG,et al.Perspectives of SLIT/ROBO signaling in placental angiogenesis[J].Histol Histopathol,2010,25(9):1181-1190.
Stollman TH,Ruers TJ,Oyen WJ,et al.New targeted probes for radioimaging of angiogenesis[J].Methods,2009,48(2):188-192.
Wang LJ,Zhao Y,Han B,et al.Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis[J].Cancer Sci,2008,99(3):510-517.
Jones CA,London NR,Chen H,et al.Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J].Nat Med,2008,14(4):448-453.
Guijarro-Munoz I,Cuesta AM,Alvarez-Cienfuegos A,et al.The axonal repellent Slit2 inhibits pericyte migration:potential implications in angiogenesis[J].Exp Cell Res,2012,318(4):371-378.
Sasaki T,Komatsu Y,Watakabe A,et al.Prefrontal-enriched SLIT1 expression in Old World monkey cortex established during the postnatal development[J].Cereb Cortex,2010,20(10):2496-2510.
Ye BQ,Geng ZH,Ma L,et al.Slit2regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation[J].J Immunol,2010,185(10):6294-6305.
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(1):19-29.
London NR,Li DY.Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm[J].Curr Opin Hematol,2011,18(3):186-190.
Dickinson RE,Duncan WC.The SLIT-ROBO pathway:a regulator of cell function with implications for the reproductive system[J].Reproduction,2010,139(4):697-704.
Duncan WC,McDonald SE,Dickinson RE,et al.Expression of the repulsive SLIT/ROBO pathway in the human endometrium and Fallopian tube[J].Mol Hum Reprod,2010,16(12):950-959.
Ma S,Liu X,Geng JG,et al.Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma[J].Am J Obstet Gynecol,2010,202(1):68.e1-68.e11.
Narayan G,Goparaju C,Arias-Pulido H,et al.Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression[J].Mol Cancer,2006,5:16.
Qiu H,Zhu J,Yu J,et al.SLIT2 is epigenetically silenced in ovarian cancers and suppresses growth when activated[J].Asian Pac J Cancer Prev,2011,12(3):791-795.
Dickinson RE,Fegan KS,Ren X,et al.Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells[J].PLoS One,2011,6(11):e27792.
Latil A,Chene L,Cochant-Priollet B,et al.Quantification of expression of netrins,slits and their receptors in human prostate tumors[J].In J Cancer,2003,103(3):306-315.
Bacon C,Endris V,Rappold G.Dynamic expression of the Slit-Robo GTPase activating protein genes during development of the murine nervous system[J].J Comp Neurol,2009,513(2):224-236.
Bauer K,Dowejko A,Bosserhoff AK,et al.Slit-2facilitates interaction of P-cadherin with Robo-3and inhibits cell mig ration in an oral squamous cell carcinoma cell line[J].Carcinogenesis,2011,32(6):935-943.
Stella MC,Trusolino L,Comoglio PM.The Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis[J].Mol Biol Cell,2009,20(2):642-657.
Donninger H,Bonome T,Radonovich M,et al.Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways[J].Oncogene,2004,23(49):8065-8077.
Kim HK,Zhang H,Li H,et al.Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10(12):1411-1420.
Schmid BC,Rezniczek GA,Fabjani G,et al.The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells[J].Breast Cancer Res Treat,2007,106(3):333-342.
Zhou WJ,Geng ZH,Chi S,et al.Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis[J].Cell Res,2011,21(4):609-626.
Liao WX,Wing DA,Geng JG,et al.Perspectives of SLIT/ROBO signaling in placental angiogenesis[J].Histol Histopathol,2010,25(9):1181-1190.
Stollman TH,Ruers TJ,Oyen WJ,et al.New targeted probes for radioimaging of angiogenesis[J].Methods,2009,48(2):188-192.
Wang LJ,Zhao Y,Han B,et al.Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis[J].Cancer Sci,2008,99(3):510-517.
Jones CA,London NR,Chen H,et al.Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability[J].Nat Med,2008,14(4):448-453.
Guijarro-Munoz I,Cuesta AM,Alvarez-Cienfuegos A,et al.The axonal repellent Slit2 inhibits pericyte migration:potential implications in angiogenesis[J].Exp Cell Res,2012,318(4):371-378.