YAP的生物學(xué)功能及其與卵巢癌相關(guān)性研究進(jìn)展

YAP的生物學(xué)功能及其與卵巢癌相關(guān)性研究進(jìn)展吳丹;王建東Hippo-YAP.YAP是該通路的主要效應(yīng)分子,在保證胚胎正常生長(zhǎng)發(fā)育、控制器官體積、維持內(nèi)環(huán)境穩(wěn)態(tài)中起到重要作用.同時(shí),YAP,YAPYAP性研究.【期刊名稱】《癌癥進(jìn)展》【年(卷),期】2017(015)008【總頁數(shù)】3頁(P851-853)【關(guān)鍵詞】Hippo;YAP;卵巢癌【作者】吳丹;王建東【作者單位】首都醫(yī)科大學(xué)附屬北京婦產(chǎn)醫(yī)院婦瘤科,北京100026;首都醫(yī)科大學(xué)附屬北京婦產(chǎn)醫(yī)院婦瘤科,北京100026【正文語種】中文【中圖分類】R737.31Hippo[1]，是一個(gè)參與胚胎正常發(fā)育、控制器官大小、維持干細(xì)胞全能性的信號(hào)傳導(dǎo)通路。Yes（Yes-associatedprotein，YAP）Hippo織器官的正常大小，維持機(jī)體內(nèi)環(huán)境的穩(wěn)態(tài)[2]。卵巢癌在女性生殖器腫瘤中病死5年生存率始終停留在20%～30%[3]，主要與卵巢癌的化療耐藥、復(fù)發(fā)有關(guān)。近年的研究表明，Hippo-YAP通路參與了卵巢癌的發(fā)生、侵襲、轉(zhuǎn)移并介導(dǎo)化療耐藥，與卵巢癌的預(yù)后密切相關(guān)[4]。YAP11q2265kDDNA1～2WW構(gòu)域、14-3-3SH3PDZWWPro-Pro-X-Tyr（PPXY）基序的配體[6TBYAPTEADYAPWWYAP1WWYAP22WWYAPYAP8.5YAPYAPYAP基因則會(huì)導(dǎo)致皮膚發(fā)育不全[8]。YAPYAP4[9]。另外，Hippo-YAPYAP及TEAD使神經(jīng)前體細(xì)胞增多，而YAP及TEAD功能性缺失則導(dǎo)致細(xì)胞凋亡增加，神經(jīng)分化提前發(fā)生[10]，該通路與神經(jīng)退行性疾病也密切相關(guān)。YAPHippo信號(hào)通路的主要效應(yīng)分子，在心臟發(fā)育中也起著重要作用，敲除YAP基因可引起YAP數(shù)量增加，使心臟體積增大，但是不能引起心肌細(xì)胞的生理性肥大[11]。YAPYAP的調(diào)節(jié)，如細(xì)胞極性、機(jī)械力學(xué)、G蛋白偶聯(lián)受體和細(xì)胞連接等[13]，在胚胎發(fā)育、控制器官大小及維持內(nèi)環(huán)境穩(wěn)態(tài)中都起著重要的作用。YAPp73、SMAD（BMP）、Bric2、Bnc5（IAP）、ErbB4PEBP2aRunx1/2Pax3TBX5[14-15]促進(jìn)HippoYAP基因被認(rèn)為是一種原癌基因。YAP14-3-3YAPYAPTEAD圍正常組織相比差異明顯[16-21]。細(xì)胞間的接觸抑制是防止細(xì)胞無限增殖的重要機(jī)制，YAPYAPYAPHippo-YAP楚，還有待進(jìn)一步的研究。卵巢癌是婦科常見的惡性腫瘤，有多種信號(hào)通路參與了卵巢癌的發(fā)生發(fā)展，如HedgehogJAK-STATEGFR王君和曲群[23YAP90.57%，而50%、65%，差異有統(tǒng)計(jì)學(xué)意義。YAPYAPYAP106YAP9YAPHall等[25]通過對(duì)卵巢癌患者分析發(fā)現(xiàn)，細(xì)胞核中YAP高表達(dá)及細(xì)胞質(zhì)中磷酸化YAP低表達(dá)者，其5年生存率較正常表達(dá)者降低50%，YAP高表達(dá)患者的無瘤生存期明顯縮短。YAP蛋白在高臨床分期和高病理分級(jí)的卵巢癌組織中陽性表達(dá)率更高[26]，提示YAP高表達(dá)與腫瘤惡性程度呈正相關(guān)。He等[27]的體內(nèi)實(shí)驗(yàn)充分說明YAP在卵巢上皮細(xì)胞內(nèi)的過度表達(dá)能促進(jìn)腫瘤生成，并且YAP的表達(dá)量與腫瘤分級(jí)及TNM分期有關(guān)，YAP的高表達(dá)與不良預(yù)后明顯相關(guān)。目前卵巢癌的治療主要是手術(shù)及術(shù)后以鉑類為主的化療，卵巢癌的化療耐藥是導(dǎo)致化療失敗，引起卵巢癌復(fù)發(fā)、轉(zhuǎn)移及病死率居高不下的關(guān)鍵因素，研究證實(shí)了抑制YAP能夠逆轉(zhuǎn)順鉑耐藥，增強(qiáng)化療敏感性，這也為卵巢癌的治療提供了新思路。研究顯示，YAP可能參與了機(jī)體表面上皮干細(xì)胞的修復(fù)，腸道干細(xì)胞及造血干細(xì)胞的調(diào)控[28-30]。YAP-TEAD2的高表達(dá)能夠維持胚胎干細(xì)胞、神經(jīng)干細(xì)胞、造血干細(xì)胞的“干性”，并且已經(jīng)成為維持“干性”的標(biāo)志物。YAPYAP癌啟動(dòng)細(xì)胞中維持干細(xì)胞全能性的關(guān)鍵蛋白Oct4在培養(yǎng)基中形成的集落也更小[31]。YAPTEAD充質(zhì)細(xì)胞的轉(zhuǎn)化（EMT），EMT是腫瘤干細(xì)胞的特點(diǎn)之一，也是腫瘤轉(zhuǎn)移中一個(gè)很重要的過程。肺癌干細(xì)胞可能通過YAP/TAZ依賴途徑促進(jìn)肺癌形成及惡性轉(zhuǎn)移[32]，卵巢癌干細(xì)胞可能是卵巢上皮細(xì)胞惡性轉(zhuǎn)化的主要原因。腫瘤干細(xì)胞的存在可能是腫瘤耐藥形成的關(guān)鍵因素，而YAP對(duì)于卵巢癌起始細(xì)胞的化療藥物抵抗性必不可少，并參與對(duì)卵巢癌起始細(xì)胞自我更新的調(diào)控[31]，在腫瘤中扮演著癌基因的角色。Hippo-YAPYAPEdgarBA.Fromcellstructuretotranscription:Hippoforgesanewpath[J].Cell,2006,124(2):267-273.吳卉,花榮,陳錦先.HippoYAP[J].實(shí)用醫(yī)學(xué)雜志,2013,29(4):515-517.BhattP,VhoraI,PatilS,etal.Roleofantibodiesindiagnosisandtreatmentofovariancancer:Basicapproachandclinicalstatus[J].JControlRelease,2016,226:148-167.HarveyKF,ZhangX,ThomasDM.TheHippopathwayandhumancancer[J].NatRevCancer,2013,13(4):246-257.ChenL,ChanSW,ZhangX,etal.StructuralbasisofYAPrecognitionbyTEAD4inthehippopathway[J].GenesDev,2010,24(3):290-300.宋娟(綜述),葉小群(審校).Hippo-YAP[J].中國(guó)腫瘤臨床,2015,42(17):876-880.Morin-KensickiEM,BooneBN,HowellM,etal.Defectsinyolksacvasculogenesis,chorioallantoicfusion,andembryonicaxiselongationinmicewithtargeteddisruptionofYap65[J].MolCellBiol,2006,26(1):77-87.[8]SchlegelmilchK,MohseniM,KirakO,etal.Yap1actsdownstreamofα-catenintocontrolepidermalproliferation[J].Cell,2011,144(5):782-795.[9]GomezM,GomezV,HergovichA.TheHippopathwayindiseaseandtherapy:cancerandbeyond[J].ClinTranslMed,2014,3:22.趙思奇,王樹坤,何晴,等.Hippo[J].生物化學(xué)與生物物理進(jìn)展,2016,43(4):383-388.vonGA,LinZ,SchlegelmilchK,etal.YAP1,thenucleartargetofHipposignaling,stimulatesheartgrowththroughcardiomyocyteproliferationbutnothypertrophy[J].ProcNatlAcadSciUSA,2012,109(7):2394-2399.[12]KawamuraK,ChengY,SuzukiN,etal.HipposignalingdisruptionandAktstimulationofovarianfolliclesforinfertilitytreatment[J].ProcNatlAcadSciUSA,2013,110(43):17474-17479.鮑乾坤,何金龍,朱毅.Hippo-YAP[J].生理科學(xué)進(jìn)展,2014,45(3):195-200.YuFX,GuanKL.TheHippopathway:regulatorsandregulations[J].GenesDev,2013,27(4):355-371.郭立達(dá),焦振霞,宋瑛,等.姜黃素誘導(dǎo)結(jié)腸癌LoVo[J].中國(guó)中藥雜志,2013,38(13):2191-2196.班媛媛,張偉,李道勝.YesBaiH,GayyedMF,Lam-HimlinDM,etal.ExpressionofYes-associatedproteinmodulatesSurvivinexpressioninprimarylivermalignancies[J].HumPathol,2012,43(9):1376-1385.XuZP,ZhuJS,ZhangQ,etal.AbreakdownoftheHippopathwayingastriccancer[J].Hepatogastroenterology,2011,58(110-111):1611-1617.[19]李曉宇,田字彬,單信芝,等.HippoYes,2013,21(28):3013-3018.TsujiuraM,MazackV,SudolM,etal.Yes-associatedprotein(YAP)modulatesoncogenicfeaturesandradiationsensitivityinendometrialcancer[J].PLoSOne,2014,9(6):e100974.SteinhardtAA,GayyedMF,KleinAP,etal.ExpressionofYes-associatedproteinincommonsolidtumors[J].HumPathol,2008,39(11):1582-1589.[22]夏燕.YAP[D].杭州:浙江大學(xué),2014.王君,曲群.YAPCREB[J].中外醫(yī)療,2014,(35):33-34;37.XiaY,ChangT,WangY,etal.YAPpromotesovariancancercelltumorigenesisandisindicativeofapoorprognosisforovariancancerpatients[J].PLoSOne,2014,9(3):e91770.HallCA,WangR,MiaoJ,etal.HippopathwayeffectorYapisanovariancanceroncogene[J].CancerRes,2010,70(21):8517-8525.Hippo-Yes,2015,22(2):125-128.HeC,LvX,HuaG,etal.YAPformsautocrineloopswiththeERBBpathwaytoregulateovariancancerinitiationandprogression[J].Oncogene,2015,34(50):6040-6054.AvruchJ,ZhouD,BardeesyN.YAPoncogeneoverexpressionsuperchargescoloncancerproliferation[J].CellCycle,2012,11(6):1090-1096.[29]TouilY,IgoudjilW,CorvaisierM,etal.Coloncancercellsescape5FUchemotherapy-inducedcelldeathbyenteringstemnessandquiescenceassociatedwiththec-Yes/YAPaxis[J].ClinCancerRes,2014,20(4):837-846.[30]GoldieSJ,MulderKW,TanDW,etal.FRMD4Aupregulationinhumansquamouscellcarcinomapromotestumorgrowthandmetastasisandisassociatedwithpoorprognosis[J].CancerRes,2012,72(13):3424-3436.[31]XiaY,ZhangYL,YuC,etal.YAP/TEADco-activatorregulatedpluripotencyandchemoresistanceinovariancancerinitiatedcells[J].PLoSOne,2014,9(11):e109575.[32]LauAN,CurtisSJ,FillmoreCM,etal.Tumor-propagatingcellsandYap/Tazactivitycontributetolungtumorprogressionandmetastasis[J].EMBOJ,2014,33(5):468-481.【相關(guān)文獻(xiàn)】EdgarBA.Fromcellstructuretotranscription:Hippoforgesanewpath[J].Cell,2006,124(2):267-273.吳卉,花榮,陳錦先.HippoYAP[J].實(shí)用醫(yī)學(xué)雜志,2013,29(4):515-517.BhattP,VhoraI,PatilS,etal.Roleofantibodiesindiagnosisandtreatmentofovariancancer:Basicapproachandclinicalstatus[J].JControlRelease,2016,226:148-167.[4]HarveyKF,ZhangX,ThomasDM.TheHippopathwayandhumancancer[J].NatRevCancer,2013,13(4):246-257.ChenL,ChanSW,ZhangX,etal.StructuralbasisofYAPrecognitionbyTEAD4inhippopathway[J].GenesDev,2010,24(3):290-300.).Hippo-YAP信號(hào)通路為靶點(diǎn)的腫瘤治療研究進(jìn)展[J國(guó)腫瘤,2015,42(17):876-880.Morin-KensickiEM,BooneBN,HowellM,etal.Defectsinyolksacvasculogenesis,chorioallantoicfusion,andembryonicaxiselongationinmicewithtargeteddisruptionofYap65[J].MolCellBiol,2006,26(1):77-87.SchlegelmilchK,MohseniM,KirakO,etal.Yap1actsdownstreamof-catenintoepidermalproliferation[J].Cell,2011,144(5):782-795.GomezM,GomezV,HergovichA.TheHippopathwayindiseaseandtherapy:cancerbeyond[J].ClinTranslMed,2014,3:22..Hippo,2016,43(4):383-388.vonGA,LinZ,SchlegelmilchK,etal.YAP1,thenucleartargetofHipposignaling,stimulatesheartgrowththroughcardiomyocyteproliferationbuthypertrophy[J].ProcNatlAcadSciUSA,2012,109(7):2394-2399.KawamuraK,ChengY,SuzukiN,etal.HipposignalingdisruptionandAktstimulationofovarianfolliclesforinfertilitytreatment[J].ProcNatlAcadSciUSA,2013,110(43):17474-17479..Hippo-YAP通路在心血管系統(tǒng)中的作用,2014,45(3):195200.YuFX,GuanKL.TheHippopathway:regulatorsandregulations[J].GenesDev,2013,27(4):355-371.LoVo細(xì)胞凋亡的作用及機(jī)制研究,2013,38(13):2191-2196..Yes),2016,10(24):3734-3738.BaiH,GayyedMF,Lam-HimlinDM,etal.ExpressionofYes-associatedproteinmodulatesSurvivinexpressioninprimarylivermalignancies[J].HumPathol,2012,43(9):1376-1385.[18]XuZP,ZhuJS,ZhangQ,etal.AbreakdownoftheHippopathwayingastriccancer[J].Hepatogastroenterology,2011,58(110-111):1611-1617..HippoYes化雜志,2013,21(28):3013-3018.TsujiuraM,MazackV,SudolM,etal.Yes-associatedprotein(YAP)modulatesoncogenicfeaturesandradiationsensitivityinendometrialcancer[J].PLoSOne,2014,9(6):e100974.[21]SteinhardtAA,GayyedMF,KleinAP,etal.ExpressionofYes-associatedproteinincommonsolidtumors[J].HumPathol,2008,39(11):1582-1589.夏燕.YAP[D].杭州:浙江大學(xué),2014.王君,曲群.YAPCREB[J].中外醫(yī)療,2014,(35):33-34;37.XiaY,ChangT,WangY,etal.YAPpromotesovariancancercelltumorigenesisandisindicativeofapoorprognosisforovariancancerpatients[J].PLoSOne,2014,9(3):e91770.[25]HallCA,WangR,MiaoJ,etal.HippopathwayeffectorYapisanovariancanceroncogene[J].CancerRes,2010,70(21):8517-8525.Hippo-Yes,2015,22(2):125-128.HeC,LvX,HuaG,etal.YAPformsautocrineloopswithth