Wnt信号通路对细胞增殖的调控
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摘要
Wnt信号通路是一种在进化上高度保守的信号通路,在机体细胞的生长、发育以及代谢平衡等过程中发挥重要作用。细胞增殖是生物体生长、发育和遗传的基础。许多研究发现,Wnt信号通路中关键分子的变化会促进或抑制细胞增殖。现综述Wnt信号通路的组成、调控机理以及Wnt信号通路对细胞增殖的调控,并讨论基于Wnt信号通路影响细胞增殖的理论开发治疗癌症药物的可能性。
Wnt signaling pathway is evolutionarily conserved, and has multiple biological functions during animal growth and development, and metabolic balance regulation. Cell proliferation is the base of genetics, growth and development. Previous studies demonstrate that alteration of Wnt signaling component either enhance or inhibit cell proliferation. In this review, the composition and regulation mechanisms of Wnt signaling pathway were summarized, and its effect on cell proliferation was reviewed. Additionally, possibility for developing new drugs targeted Wnt signaling pathway for cancer treatment was discussed.
Wnt signaling pathway is evolutionarily conserved, and has multiple biological functions during animal growth and development, and metabolic balance regulation. Cell proliferation is the base of genetics, growth and development. Previous studies demonstrate that alteration of Wnt signaling component either enhance or inhibit cell proliferation. In this review, the composition and regulation mechanisms of Wnt signaling pathway were summarized, and its effect on cell proliferation was reviewed. Additionally, possibility for developing new drugs targeted Wnt signaling pathway for cancer treatment was discussed.
引文
[1]Berndt JD,Moon RT.Making a point with Wnt signals.Science,2013,339:1388-9
[2]Nusse R,Brown A,Papkoff J,et al.A new nomenclature for int-1 and related genes:the Wnt gene family.Cell,1991,64:231-2
[3]Yang-Snyder J,Miller JR,Brown JD,et al.A frizzled homolog functions in a vertebrate Wnt signaling pathway.Curr Biol,1996,6:1302-6
[4]Willert K,Brown JD,Danenberg E,et al.Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature,2003,423:448-52
[5]Hart MJ,de los Santos R,Albert IN,et al.Downregulation ofβ-catenin by human Axin and its association with the APC tumor suppressor,β-catenin and GSK3β.Curr Biol,1998,8:573-81
[6]Ikeda S,Kishida S,Yamamoto H,et al.Axin,a negative regulator of the Wnt signaling pathway,forms a complex with GSK-3βandβ-catenin and promotes GSK-3β-dependent phosphorylation ofβ-catenin.EMBO J,1998,17:1371-84
[7]Aberle H,Bauer A,Stappert J,et al.β-catenin is a target for the ubiquitin-proteasome pathway.EMBO J,1997,16:3797-804
[8]Cox RT,Peifer M.Wingless signaling:the inconvenient complexities of life.Curr Biol,1998,8:R140-4
[9]Tolwinski NS,Wehrli M,Rives A,et al.Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3βactivity.Dev Cell,2003,4:407-18
[10]Noutsou M,Duarte AMS,Anvarian Z,et al.Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded.J Mol Biol,2011,405:773-86
[11]Minde DP,Anvarian Z,Rüdiger SGD,et al.Messing up disorder:how do missense mutations in the tumor suppressor protein APC lead to cancer?Mol Cancer,2011,10:101
[12]Aoki M,Yokota T,Sugiura I,et al.Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3β.Acta Crystallogr D Biol Crystallogr,2004,60:439-46
[13]Davidson G,Wu W,Shen J,et al.Casein kinase 1γcouples Wnt receptor activation to cytoplasmic signal transduction.Nature,2005,438:867-72
[14]杨春华,刘英,伍会健.β-Trcp与肿瘤关系的研究.中国细胞生物学学报,2011,33:796-801
[15]MacDonald BT,Tamai K,He X.Wnt/β-catenin signaling:components,mechanisms,and diseases.Dev Cell,2009,17:9-26
[16]李明聪,王占祥.Pygopus研究进展.国际肿瘤学杂志,2015,42:364-6
[17]Veeman MT,Slusarski DC,Kaykas A,et al.Zebrafish prickle,a modulator of noncanonical Wnt/Fz signaling,regulates gastrulation movements.Curr Biol,2003,13:680-5
[18]Liu C,Lin C,Whitaker DT,et al.Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis.Hum Mol Genet,2013,22:2234-46
[19]Tao H,Inoue K,Kiyonari H,et al.Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis.Dev Biol,2012,364:138-48
[20]Fanto M,McNeill H.Planar polarity from flies to vertebrates.J Cell Sci,2004,117:527-33
[21]Nakashima T,Liu D,Nakano J,et al.Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients.Oncol Rep,2008,19:203-9
[22]Clevers H,Nusse R.Wnt/β-catenin signaling and disease.Cell,2012,149:1192-205
[23]Kim J,Kim DW,Chang W,et al.Wnt5a is secreted by follicular dendritic cells to protect germinal center B cells via Wnt/Ca2+/NFAT/NF-κB-B cell lymphoma 6 signaling.J Immunol,2012,188:182-9
[24]De A.Wnt/Ca2+signaling pathway:a brief overview.Acta Biochim Biophys Sin(Shanghai),2011,43:745-56
[25]Endo M,Nishita M,Minami Y.Analysis of Wnt/planar cell polarity pathway in cultured cells.Methods Mol Biol,2012,839:201-14
[26]Gebruers E,Corderomaldonado ML,Gray AI,et al.Aphenotypic screen in zebrafish identifies a novel smallmolecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling.PLoSOne,2013,8:e83293
[27]李春艳,高宁,侯颖春.经典Wnt信号通路与人类肿瘤.中国生物化学与分子生物学报,2014,30:447-52
[28]Wu J,Liu S,Meng H,et al.Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/β-catenin pathway in vitro.Stem Cell Res,2017,21:74-84
[29]陈宗正,仇杨,吴国芳,等.EGCG通过抑制Wnt/β-catenin信号通路调节猪骨骼肌卫星细胞的增殖和分化.中国生物化学与分子生物学报,2012,28:645-52
[30]Clevers H,Loh KM,Nusse R.An integral program for tissue renewal and regeneration:Wnt signaling and stem cell control.Science,2014,346:1248012
[31]van Es JH,Haegebarth A,Kujala P,et al.A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic selfrenewal.Mol Cell Biol,2012,32:1918-27
[32]Barker N,Van Es JH,Kuipers J,et al.Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature,2007,449:1003-7
[33]Lim X,Tan SH,Koh WL,et al.Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science,2013,342:1226-30
[34]Xu HT,Wei Q,Liu Y,et al.Overexpression of axin down regulates TCF-4 and inhibits the development of lung cancer.Ann Surg Oncol,2007,14:3251-9
[35]Kim JC,Koo KH,Roh SA,et al.Genetic and epigenetic changes in the APC gene in sporadic colorectal carcinoma with synchronous adenoma.Int J Colorectal Dis,2003,18:203-9
[36]Braunschweig L,Meyer AK,Wagenführ L,et al.Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling.Mol Cell Neurosci,2015,67:84-92
[37]Yang XT,Bi YY,Chen ET,et al.Overexpression of Wnt3a facilitates the proliferation and neural differentiation of neural stem cells in vitro and after transplantation into an injured rat retina.J Neurosci Res,2014,92:148-61
[38]Hosoya T,Sakai F,Yamashita M,et al.Lactobacillus helveticus SBT2171 inhibits lymphocyte proliferation by regulation of the JNK signaling pathway.PLoS One,2014,9:e108360
[39]Wu F,Lv T,Chen G,et al.Epigenetic silencing of DUSP9induces the proliferation of human gastric cancer by activating JNK signaling.Oncol Rep,2015,34:121-8
[40]Baksh D,Boland GR.Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation.JCell Biochem,2007,101:1109-24
[41]解晓东,虞德兵,于敏莉,等.siRNA干扰Wnt11对鸭成肌细胞增殖的影响.畜牧与兽医,2017,49:42-6
[42]Du J,Xu R.RORα,a potential tumor suppressor and therapeutic target of breast cancer.Int J Mol Sci,2012,13:15755-66
[43]Heallen T,Zhang M,Wang J,et al.Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.Science,2011,332:458-61
[44]Rosenbluh J,Nijhawan D,Cox A G,et al.β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.Cell,2012,151:1457-73
[45]Dou GR,Wang YC,Hu XB,et al.RBP-J,the transcription factor downstream of Notch receptors,is essential for the maintenance of vascular homeostasis in adult mice.FASEB J,2008,22:1606-17
[46]Suchting S,Freitas C,le Noble F,et al.The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.Proc Natl Acad Sci USA,2007,104:3225-30
[47]Jeong WJ,Yoon J,Park JC,et al.Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis.Sci Signal,2012,5:ra30
[48]Schwitalla S,Fingerle AA,Cammareri P,et al.Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell,2013,152:25-38
[49]杨升,卢辉山.Wnt信号通路与消化道肿瘤关系的研究进展.世界华人消化杂志,2007,27:2880-4
[50]缪成贵,黄成,黄艳,等.Wnt调控类风湿性关节炎研究进展.中国药理学通报,2013,2:149-53
[51]Minde DP,Radli M,Forneris F,et al.Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations.PLoSOne,2013,8:e77257
[52]Liu H,Shi H,Fan Q,et al.Cyclin Y regulates the proliferation,migration,and invasion of ovarian cancer cells via Wnt signaling pathway.Tumor Biol,2016,37:10161-75
[53]Xie Y,Wang B.Downregulation of TNFAIP2 suppresses proliferation and metastasis in esophageal squamous cell carcinoma through activation of the Wnt/β-catenin signaling pathway.Oncol Rep,2017,37:2920-8
[54]Wang Q,Wang X,Zhang CB.Lentivirus mediated GOLPH3 shRNA inhibits growth and metastasis of esophageal squamous cancer.Asian Pac J Cancer Prev,2013,14:5391-6
[55]Zhang Y.Ganoderma lucidum(Reishi)suppresses proliferation and migration of breast cancer cells via inhibiting Wnt/β-catenin signaling.Biochem Biophys Res Commun,2017,488:679-84
[56]万雪莲,马菲菲,马红莹,等.HepaCAM通过Wnt/β-catenin信号通路抑制膀胱癌细胞T24的增殖.中国细胞生物学学报,2015,37:683-8
[57]Anastas JN,Moon RT.WNT signalling pathways as therapeutic targets in cancer.Nat Rev Cancer,2013,13:11-26
[58]董燕.以Wnt信号通路Porcupine蛋白为靶点的小分子抑制剂的设计、合成及活性研究[D].苏州:苏州大学,2016
[59]Wang W,Liu H,Wang S,et al.A diterpenoid derivative15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis.Cell Res,2011,21:730-40
[60]Masuda M,Uno Y,Ohbayashi N,et al.TNIK inhibition abrogates colorectal cancer stemness.Nat Commun,2016,7:12586
[61]Liu J,Pan S,Hsieh MH,et al.Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.Proc Natl Acad Sci USA,2013,110:20224-9
[62]Madan B,Ke Z,Harmston N,et al.Wnt addiction of genetically defined cancers reversed by PORCNinhibition.Oncogene,2016,35:2197-207
[2]Nusse R,Brown A,Papkoff J,et al.A new nomenclature for int-1 and related genes:the Wnt gene family.Cell,1991,64:231-2
[3]Yang-Snyder J,Miller JR,Brown JD,et al.A frizzled homolog functions in a vertebrate Wnt signaling pathway.Curr Biol,1996,6:1302-6
[4]Willert K,Brown JD,Danenberg E,et al.Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature,2003,423:448-52
[5]Hart MJ,de los Santos R,Albert IN,et al.Downregulation ofβ-catenin by human Axin and its association with the APC tumor suppressor,β-catenin and GSK3β.Curr Biol,1998,8:573-81
[6]Ikeda S,Kishida S,Yamamoto H,et al.Axin,a negative regulator of the Wnt signaling pathway,forms a complex with GSK-3βandβ-catenin and promotes GSK-3β-dependent phosphorylation ofβ-catenin.EMBO J,1998,17:1371-84
[7]Aberle H,Bauer A,Stappert J,et al.β-catenin is a target for the ubiquitin-proteasome pathway.EMBO J,1997,16:3797-804
[8]Cox RT,Peifer M.Wingless signaling:the inconvenient complexities of life.Curr Biol,1998,8:R140-4
[9]Tolwinski NS,Wehrli M,Rives A,et al.Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3βactivity.Dev Cell,2003,4:407-18
[10]Noutsou M,Duarte AMS,Anvarian Z,et al.Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded.J Mol Biol,2011,405:773-86
[11]Minde DP,Anvarian Z,Rüdiger SGD,et al.Messing up disorder:how do missense mutations in the tumor suppressor protein APC lead to cancer?Mol Cancer,2011,10:101
[12]Aoki M,Yokota T,Sugiura I,et al.Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3β.Acta Crystallogr D Biol Crystallogr,2004,60:439-46
[13]Davidson G,Wu W,Shen J,et al.Casein kinase 1γcouples Wnt receptor activation to cytoplasmic signal transduction.Nature,2005,438:867-72
[14]杨春华,刘英,伍会健.β-Trcp与肿瘤关系的研究.中国细胞生物学学报,2011,33:796-801
[15]MacDonald BT,Tamai K,He X.Wnt/β-catenin signaling:components,mechanisms,and diseases.Dev Cell,2009,17:9-26
[16]李明聪,王占祥.Pygopus研究进展.国际肿瘤学杂志,2015,42:364-6
[17]Veeman MT,Slusarski DC,Kaykas A,et al.Zebrafish prickle,a modulator of noncanonical Wnt/Fz signaling,regulates gastrulation movements.Curr Biol,2003,13:680-5
[18]Liu C,Lin C,Whitaker DT,et al.Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis.Hum Mol Genet,2013,22:2234-46
[19]Tao H,Inoue K,Kiyonari H,et al.Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis.Dev Biol,2012,364:138-48
[20]Fanto M,McNeill H.Planar polarity from flies to vertebrates.J Cell Sci,2004,117:527-33
[21]Nakashima T,Liu D,Nakano J,et al.Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients.Oncol Rep,2008,19:203-9
[22]Clevers H,Nusse R.Wnt/β-catenin signaling and disease.Cell,2012,149:1192-205
[23]Kim J,Kim DW,Chang W,et al.Wnt5a is secreted by follicular dendritic cells to protect germinal center B cells via Wnt/Ca2+/NFAT/NF-κB-B cell lymphoma 6 signaling.J Immunol,2012,188:182-9
[24]De A.Wnt/Ca2+signaling pathway:a brief overview.Acta Biochim Biophys Sin(Shanghai),2011,43:745-56
[25]Endo M,Nishita M,Minami Y.Analysis of Wnt/planar cell polarity pathway in cultured cells.Methods Mol Biol,2012,839:201-14
[26]Gebruers E,Corderomaldonado ML,Gray AI,et al.Aphenotypic screen in zebrafish identifies a novel smallmolecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling.PLoSOne,2013,8:e83293
[27]李春艳,高宁,侯颖春.经典Wnt信号通路与人类肿瘤.中国生物化学与分子生物学报,2014,30:447-52
[28]Wu J,Liu S,Meng H,et al.Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/β-catenin pathway in vitro.Stem Cell Res,2017,21:74-84
[29]陈宗正,仇杨,吴国芳,等.EGCG通过抑制Wnt/β-catenin信号通路调节猪骨骼肌卫星细胞的增殖和分化.中国生物化学与分子生物学报,2012,28:645-52
[30]Clevers H,Loh KM,Nusse R.An integral program for tissue renewal and regeneration:Wnt signaling and stem cell control.Science,2014,346:1248012
[31]van Es JH,Haegebarth A,Kujala P,et al.A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic selfrenewal.Mol Cell Biol,2012,32:1918-27
[32]Barker N,Van Es JH,Kuipers J,et al.Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature,2007,449:1003-7
[33]Lim X,Tan SH,Koh WL,et al.Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science,2013,342:1226-30
[34]Xu HT,Wei Q,Liu Y,et al.Overexpression of axin down regulates TCF-4 and inhibits the development of lung cancer.Ann Surg Oncol,2007,14:3251-9
[35]Kim JC,Koo KH,Roh SA,et al.Genetic and epigenetic changes in the APC gene in sporadic colorectal carcinoma with synchronous adenoma.Int J Colorectal Dis,2003,18:203-9
[36]Braunschweig L,Meyer AK,Wagenführ L,et al.Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling.Mol Cell Neurosci,2015,67:84-92
[37]Yang XT,Bi YY,Chen ET,et al.Overexpression of Wnt3a facilitates the proliferation and neural differentiation of neural stem cells in vitro and after transplantation into an injured rat retina.J Neurosci Res,2014,92:148-61
[38]Hosoya T,Sakai F,Yamashita M,et al.Lactobacillus helveticus SBT2171 inhibits lymphocyte proliferation by regulation of the JNK signaling pathway.PLoS One,2014,9:e108360
[39]Wu F,Lv T,Chen G,et al.Epigenetic silencing of DUSP9induces the proliferation of human gastric cancer by activating JNK signaling.Oncol Rep,2015,34:121-8
[40]Baksh D,Boland GR.Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation.JCell Biochem,2007,101:1109-24
[41]解晓东,虞德兵,于敏莉,等.siRNA干扰Wnt11对鸭成肌细胞增殖的影响.畜牧与兽医,2017,49:42-6
[42]Du J,Xu R.RORα,a potential tumor suppressor and therapeutic target of breast cancer.Int J Mol Sci,2012,13:15755-66
[43]Heallen T,Zhang M,Wang J,et al.Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.Science,2011,332:458-61
[44]Rosenbluh J,Nijhawan D,Cox A G,et al.β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.Cell,2012,151:1457-73
[45]Dou GR,Wang YC,Hu XB,et al.RBP-J,the transcription factor downstream of Notch receptors,is essential for the maintenance of vascular homeostasis in adult mice.FASEB J,2008,22:1606-17
[46]Suchting S,Freitas C,le Noble F,et al.The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.Proc Natl Acad Sci USA,2007,104:3225-30
[47]Jeong WJ,Yoon J,Park JC,et al.Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis.Sci Signal,2012,5:ra30
[48]Schwitalla S,Fingerle AA,Cammareri P,et al.Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell,2013,152:25-38
[49]杨升,卢辉山.Wnt信号通路与消化道肿瘤关系的研究进展.世界华人消化杂志,2007,27:2880-4
[50]缪成贵,黄成,黄艳,等.Wnt调控类风湿性关节炎研究进展.中国药理学通报,2013,2:149-53
[51]Minde DP,Radli M,Forneris F,et al.Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations.PLoSOne,2013,8:e77257
[52]Liu H,Shi H,Fan Q,et al.Cyclin Y regulates the proliferation,migration,and invasion of ovarian cancer cells via Wnt signaling pathway.Tumor Biol,2016,37:10161-75
[53]Xie Y,Wang B.Downregulation of TNFAIP2 suppresses proliferation and metastasis in esophageal squamous cell carcinoma through activation of the Wnt/β-catenin signaling pathway.Oncol Rep,2017,37:2920-8
[54]Wang Q,Wang X,Zhang CB.Lentivirus mediated GOLPH3 shRNA inhibits growth and metastasis of esophageal squamous cancer.Asian Pac J Cancer Prev,2013,14:5391-6
[55]Zhang Y.Ganoderma lucidum(Reishi)suppresses proliferation and migration of breast cancer cells via inhibiting Wnt/β-catenin signaling.Biochem Biophys Res Commun,2017,488:679-84
[56]万雪莲,马菲菲,马红莹,等.HepaCAM通过Wnt/β-catenin信号通路抑制膀胱癌细胞T24的增殖.中国细胞生物学学报,2015,37:683-8
[57]Anastas JN,Moon RT.WNT signalling pathways as therapeutic targets in cancer.Nat Rev Cancer,2013,13:11-26
[58]董燕.以Wnt信号通路Porcupine蛋白为靶点的小分子抑制剂的设计、合成及活性研究[D].苏州:苏州大学,2016
[59]Wang W,Liu H,Wang S,et al.A diterpenoid derivative15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis.Cell Res,2011,21:730-40
[60]Masuda M,Uno Y,Ohbayashi N,et al.TNIK inhibition abrogates colorectal cancer stemness.Nat Commun,2016,7:12586
[61]Liu J,Pan S,Hsieh MH,et al.Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.Proc Natl Acad Sci USA,2013,110:20224-9
[62]Madan B,Ke Z,Harmston N,et al.Wnt addiction of genetically defined cancers reversed by PORCNinhibition.Oncogene,2016,35:2197-207