SLIT/ROBO信号通路在女性生殖系统的研究进展
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摘要
分泌性糖蛋白SLIT及其受体ROBO信号作为神经轴突导向分子在神经系统发育过程中具有排斥神经细胞迁移的作用,另外SLIT/robo信号介导细胞迁移,细胞凋亡及血管形成,在肺、肝及乳腺形成过程中有关键性作用。Slit/robo信号在组织形态学发生中的调节异常可导致肿瘤发生。Slit/robo信号通路失活与肿瘤形成及转移有关。最近研究显示slit/robo信号在女性生殖系统形成及疾病发展过程中亦有重要作用。Slit/robo信号家族成员大多数在卵巢中表达。Slits与robos受甾体激素的调节,在女性成人生殖器官例如卵巢、子宫内膜可调节细胞生理功能。在卵巢癌、子宫内膜癌及宫颈癌形成过程中Slits与robos家族成员异常表达。本文综合论述了slit/robo在女性生殖系统形成,生理及病理等方面的作用,对其深入研究具有重要意义。
The secreted SLIT glycoproteins and their roundabout(ROBO)receptors were originally identified as important axon guidance molecules. They functions as a repulsive cue in preventing axons from migrating to inappropriate locations during the assembly of the nervous system. In addition the SLIT/ROBO interaction is involved in the regulation of cell migration,cell death and angiogenesis and,as such,has a pivotal role during the development of other tissues such as the lung,kidney,liver and breast. The cellular functions that the SLIT/ROBO pathway controls during tissue morphogenesis are processes that are dysregulated during cancer development. Therefore inactivation of certain SLITs and ROBOs is associated with advanced tumour formation and migration. Recent research has indicated SLIT/ROBO pathway could also have important functions in the reproductive system. The SLITs and ROBOs also appear to be regulated by steroid hormones and regulated physiological cell functions in adult reproductive tissues such as the ovary and endometrium. Furthermore several SLITs and ROBOs are aberrantly expressed during the development of ovarian,endometrial,cervical cancer. This review will examine the roles this pathway could have in the development,physiology and pathology of the reproductive system and that could further dissect the influence of the SLIT/ROBO pathway in reproduction.
The secreted SLIT glycoproteins and their roundabout(ROBO)receptors were originally identified as important axon guidance molecules. They functions as a repulsive cue in preventing axons from migrating to inappropriate locations during the assembly of the nervous system. In addition the SLIT/ROBO interaction is involved in the regulation of cell migration,cell death and angiogenesis and,as such,has a pivotal role during the development of other tissues such as the lung,kidney,liver and breast. The cellular functions that the SLIT/ROBO pathway controls during tissue morphogenesis are processes that are dysregulated during cancer development. Therefore inactivation of certain SLITs and ROBOs is associated with advanced tumour formation and migration. Recent research has indicated SLIT/ROBO pathway could also have important functions in the reproductive system. The SLITs and ROBOs also appear to be regulated by steroid hormones and regulated physiological cell functions in adult reproductive tissues such as the ovary and endometrium. Furthermore several SLITs and ROBOs are aberrantly expressed during the development of ovarian,endometrial,cervical cancer. This review will examine the roles this pathway could have in the development,physiology and pathology of the reproductive system and that could further dissect the influence of the SLIT/ROBO pathway in reproduction.
引文
[1]Rothberg JM,Jacobs JR,Goodman CS,et al.slit:an extracellular protein necessary for development of midline glia and comissural axon pathways contains both EGF and LRR domains[J].Genes Dev,1990,4(12A):2169-2187.
[2]Andrews W,et al.The role of Slit/robo signaling in the generation,migration and morphological differentitation of cortical interneurons[J].Dvelopmental Biology,2010,313:649-658.
[3]吴婷,王伟章,耿建国,等.Slit/Robo信号通路在肿瘤发生的重要作用[J].细胞生物学杂志,2009,31(4):486-490.
[4]倪伟,王浩宇.Slit/robo信号在血管新生及内皮细胞迁移中作用的研究进展[J].心血管病学进展,2012,33(5):670-672.
[5]Chedotal A,Kerian G,Moreau-Fauvarque C.The brain within the tumor:new roles for axon guidance molecules in cancers[J].Cell Death and Differentiation,2005,12:1044-1056.
[6]Dickinson RE,Myers M,Duncan WC.Novel regulated expression of the SLIT/ROBO pathway in the arovary:possible role during luteolysis in women[J].Endocrinology,2008,149:5024-5034.
[7]Dickinson RE,Hryhorskyi L,Tremewan H,et al.Involvement of the SLIT/ROBO pathway in follicle development in fetal ovary[J].Reproduction,2010,139:395-407.
[8]Dickinson RE,Fegan KS,Hillier SG.Steroid regulated expression of the SLIT/ROBO pathway in human ovarian surface epithelial cells and ovarian cancer[C].Proceedings of the Society for Gynecologic Inverstigation,56th Annual Meeting,Glagow,UK Abstract,2009.73.
[9]Duncan WC,et al.Luter development and luteolysis in the primate corpus luteum[J].Animal Reproduction,2009,6:34-36.
[10]Helvering LM,Liu R,Kulkarni NH,et al.Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and esrogen but not raloxifene[J].Molecular Phamacology,2005,68:1225-1238.
[11]Hinck L.The versatile roles of axon guidance cues in tissue morphogenesis[J].Development Cell,2004,7:783-793.
[12]Kim HK,Zhang H,Li H,et al.Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10:1411-1420.
[13]Leung PC&Choi JH.Endocrine signaling in ovarian surface epithelium and cancer[J].Human Reproduction Update,2007,13:143-162.
[14]Liao W-X,Zhang H-H,Feng L,et al.Slit/robo signaling promotes placemetal artery endothelial cell angiogenesis via activation of multiple intracellular signalling pathways[C].Proceedings of the Society for Gynecologic investigation,56th Annual Meeting,Glasgow,UK,Abstract,2009.668.
[15]Ma S,Liu X,Geng JG&Guo S-W.Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma[J].American Journal of Obstertrics and Gynecology,2010,202:68el-68e11.
[16]Shen FH,Liu XS,Geng,et al.Increased immunorecativity to SLIT/ROBO1 in ovarian endometriomas.A likely constituent biomarker for recurrence[J].2009,2:479-488.
[17]Myers M,et al.Role of luteal glucocorticoid metabolism during maternal recognition of pregnancy in women[J].Endocrinology,2007,148:5769-5779.
[18]Narayan G,et al.Promoter hypermethylation-mediated inactivation of multiple Slit/robo pathway genes in cervical cancer progression[J].Molecular Cancer,2006,5:16.
[19]Prasad A,Fernandis AZ,Rao Y&Ganju RK.Slit proteinmediated inhibition of CXCR4-induced chemotactic and chemoinvasive siganaling pathways in breast cancer cells[J].Jounal of Biological Chemistry,2004,279:9115-9124.
[20]Saegusa M,Machida D&Okayasu I.Loss of DCC gene expression during ovarian tumorigenesis:relation to tumour differentitation and progression[J].British Jounal of Cancer,2000,82:571-578.
[21]Seth P,Lin Y,Hanai J,et al.Magic roundabout,a tumor endothelial marker:expression and signaling[J].Biochemical and Biophysical Research Communications,2005,332:533-541.
[22]Shen F,et al.Increased immunoreactivity to SLIT/ROBO1in ovarian endometriomas:a likely constituent biomarker for recurrence[J].American Journal of Pathology,2009,175:479-488.
[23]Sing RK,Indra D,Mitra S,et al.Deletions in chromosome 4differentially associated with the development of cervical Cancer:evidence of slit2 as a candidate tumor suppressor gene[J].Human Genetics,2007,122:71-81.
[24]Strickland P,Shin GC,Plump A,et al.Slit2 and netrin 1 act synergistically as adhesion cues to generate tubar bi-layers during ductal morphogenesis[J].Development,2006,133:823-832.
[25]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.
[2]Andrews W,et al.The role of Slit/robo signaling in the generation,migration and morphological differentitation of cortical interneurons[J].Dvelopmental Biology,2010,313:649-658.
[3]吴婷,王伟章,耿建国,等.Slit/Robo信号通路在肿瘤发生的重要作用[J].细胞生物学杂志,2009,31(4):486-490.
[4]倪伟,王浩宇.Slit/robo信号在血管新生及内皮细胞迁移中作用的研究进展[J].心血管病学进展,2012,33(5):670-672.
[5]Chedotal A,Kerian G,Moreau-Fauvarque C.The brain within the tumor:new roles for axon guidance molecules in cancers[J].Cell Death and Differentiation,2005,12:1044-1056.
[6]Dickinson RE,Myers M,Duncan WC.Novel regulated expression of the SLIT/ROBO pathway in the arovary:possible role during luteolysis in women[J].Endocrinology,2008,149:5024-5034.
[7]Dickinson RE,Hryhorskyi L,Tremewan H,et al.Involvement of the SLIT/ROBO pathway in follicle development in fetal ovary[J].Reproduction,2010,139:395-407.
[8]Dickinson RE,Fegan KS,Hillier SG.Steroid regulated expression of the SLIT/ROBO pathway in human ovarian surface epithelial cells and ovarian cancer[C].Proceedings of the Society for Gynecologic Inverstigation,56th Annual Meeting,Glagow,UK Abstract,2009.73.
[9]Duncan WC,et al.Luter development and luteolysis in the primate corpus luteum[J].Animal Reproduction,2009,6:34-36.
[10]Helvering LM,Liu R,Kulkarni NH,et al.Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and esrogen but not raloxifene[J].Molecular Phamacology,2005,68:1225-1238.
[11]Hinck L.The versatile roles of axon guidance cues in tissue morphogenesis[J].Development Cell,2004,7:783-793.
[12]Kim HK,Zhang H,Li H,et al.Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma[J].Neoplasia,2008,10:1411-1420.
[13]Leung PC&Choi JH.Endocrine signaling in ovarian surface epithelium and cancer[J].Human Reproduction Update,2007,13:143-162.
[14]Liao W-X,Zhang H-H,Feng L,et al.Slit/robo signaling promotes placemetal artery endothelial cell angiogenesis via activation of multiple intracellular signalling pathways[C].Proceedings of the Society for Gynecologic investigation,56th Annual Meeting,Glasgow,UK,Abstract,2009.668.
[15]Ma S,Liu X,Geng JG&Guo S-W.Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma[J].American Journal of Obstertrics and Gynecology,2010,202:68el-68e11.
[16]Shen FH,Liu XS,Geng,et al.Increased immunorecativity to SLIT/ROBO1 in ovarian endometriomas.A likely constituent biomarker for recurrence[J].2009,2:479-488.
[17]Myers M,et al.Role of luteal glucocorticoid metabolism during maternal recognition of pregnancy in women[J].Endocrinology,2007,148:5769-5779.
[18]Narayan G,et al.Promoter hypermethylation-mediated inactivation of multiple Slit/robo pathway genes in cervical cancer progression[J].Molecular Cancer,2006,5:16.
[19]Prasad A,Fernandis AZ,Rao Y&Ganju RK.Slit proteinmediated inhibition of CXCR4-induced chemotactic and chemoinvasive siganaling pathways in breast cancer cells[J].Jounal of Biological Chemistry,2004,279:9115-9124.
[20]Saegusa M,Machida D&Okayasu I.Loss of DCC gene expression during ovarian tumorigenesis:relation to tumour differentitation and progression[J].British Jounal of Cancer,2000,82:571-578.
[21]Seth P,Lin Y,Hanai J,et al.Magic roundabout,a tumor endothelial marker:expression and signaling[J].Biochemical and Biophysical Research Communications,2005,332:533-541.
[22]Shen F,et al.Increased immunoreactivity to SLIT/ROBO1in ovarian endometriomas:a likely constituent biomarker for recurrence[J].American Journal of Pathology,2009,175:479-488.
[23]Sing RK,Indra D,Mitra S,et al.Deletions in chromosome 4differentially associated with the development of cervical Cancer:evidence of slit2 as a candidate tumor suppressor gene[J].Human Genetics,2007,122:71-81.
[24]Strickland P,Shin GC,Plump A,et al.Slit2 and netrin 1 act synergistically as adhesion cues to generate tubar bi-layers during ductal morphogenesis[J].Development,2006,133:823-832.
[25]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.