甲狀旁腺激素相關(guān)蛋白與消化系腫瘤的關(guān)系

甲狀旁腺激素相關(guān)蛋白與消化系腫瘤的關(guān)系何淑英;白嵐【摘要】甲狀旁腺激素相關(guān)蛋白(PTHrP)是由多種組織細(xì)胞分泌的一種活性分子,具有廣泛的生物學(xué)功效.研究發(fā)現(xiàn),多種消化道腫瘤組織過表達(dá)PTHrP,本文就PTHrP與消化系腫瘤的關(guān)系作一綜述.【期刊名稱】《現(xiàn)代消化及介入診療》【年(卷),期】2015(020)001【總頁數(shù)】4頁(P73-76)【關(guān)鍵詞】甲狀旁腺激素相關(guān)蛋白;惡性腫瘤;消化系統(tǒng)【作者】何淑英;白嵐【作者單位】510515南方醫(yī)科大學(xué)南方醫(yī)院消化內(nèi)科;510515南方醫(yī)科大學(xué)南方醫(yī)院惠僑科【正文語種】中文甲狀旁腺激素相關(guān)蛋白（PTHrP）最先是在惡性腫瘤伴發(fā)高鈣血癥的患者中發(fā)現(xiàn)，因其功能和基因結(jié)構(gòu)類似甲狀旁腺激素（PTH）而命名為PTHrP[1-2]，最初分離的純化PTHrP來源于肺癌、腎癌以及乳腺癌細(xì)胞株[3-5]。對其基因結(jié)構(gòu)研究發(fā)現(xiàn)，PTHrP通過轉(zhuǎn)錄、翻譯、修飾等基因過程，最后生成N端、中間區(qū)域或C端的成熟肽，最后通過自分泌、旁分泌、胞分泌方式結(jié)合于靶細(xì)胞的PTH受體（PTH1R）而起作用[6-7]。最初認(rèn)為它的靶器官主要為骨骼和腎，現(xiàn)在人們發(fā)現(xiàn)PTHrP分布廣泛，功能不僅僅局限于調(diào)節(jié)鈣磷的代謝，越來越多的研究證實PTHrP與胚胎發(fā)育、乳腺發(fā)育、平滑肌舒張、毛發(fā)發(fā)育及表皮分化等有關(guān)[8]。除了正常組織外，PTHrP在許多存在骨轉(zhuǎn)移的腫瘤中表達(dá)-人消化系統(tǒng)腫瘤組織如胃癌、大腸癌、肝癌、胰腺癌和胰腺內(nèi)分泌腫瘤等也同樣表達(dá)，并且一般說來PTHrP一般與低分化、腫瘤進(jìn)展以及骨轉(zhuǎn)移有關(guān)，但不同腫瘤組織研究結(jié)果不盡相同。提示PTHrP可能有組織特異性[9]。本文將就PTHrP與消化道腫瘤做一簡要概述。胃癌患者伴發(fā)高鈣血癥（HHM）的報導(dǎo)逐漸增多，通過免疫組織化學(xué)和免疫放射PTHrPPTH1RPTHrP的表達(dá)水平也升高[10-11]，同時日本學(xué)者從低分化胃腺癌組織中分離建立的細(xì)胞IGSK-3PTHrP[12]，以上證據(jù)表PTHrPPTHrPHHMPTHrPPTHrP10095.545%，同時發(fā)現(xiàn)癌組織侵潤較深的部位PTHrPPTHrPPTHrP，然而低分PTHrP[14]。CuipingLiuPTHrPcells）[15]。但目前除了有關(guān)內(nèi)切蛋白酶-弗林蛋白酶（Furin）PTHrPPTHrPPTHrPPTHrPPTHrP，而在大PTHrP94.4PTHrPPTHrP移和Duke′s分期明顯相關(guān)，這些證據(jù)支持PTHrP與大腸癌的發(fā)生、分化、進(jìn)展和預(yù)后相關(guān)[9,17]。JACarron1PTHrPPTH1RiaoliShenPTHrPLovoPTHrPAKT3[20-21]，在此基礎(chǔ)上RamanjaneyaV.MulaPTHrPAKT64Rac1Rac-specificTiam1[22]。以上實驗結(jié)果同時在裸鼠的異體移植瘤生長實驗中得到了驗證[21]。MaríaJuliaMartínPTHrPERK1/2，αp38MAPK，andPI3K[22]。針對PTHrP在結(jié)腸癌發(fā)揮作用的機(jī)制，Bhatia等證明PTHrP通過核定位信號（NLS）發(fā)揮胞分泌作用，并產(chǎn)生一系列生物學(xué)功能[23]。有趣的是在另外一株結(jié)腸癌細(xì)胞（HT-29）PTHrP51PTHrPPTHrPRoskamsT2422PTHrP100%，而肝細(xì)胞型肝癌和PTHrPPTHrPPTHrP[25]。但是臨HHM4.5%HHM2HHM[26]，而原發(fā)于肝臟的鱗癌伴發(fā)HHM并能分泌PTHrP的報導(dǎo)也有少數(shù)[27]。以上臨床資料說明PTHrP和肝癌在某種程度上可能存在著某種關(guān)系，關(guān)于其中的具體機(jī)制，LinWangPTHrPGPTHrPPTHrPTGF-βCaoHep3BPTHrPTGF-β[30PTHrP能促進(jìn)肝癌的發(fā)展，但是也有研究得出相反的結(jié)果，LiHHepG2PTHrPPTH1RPTHrPHepG2[29]。綜上所述，目前對肝癌的研究較少，PTHrP要更多的證據(jù)。胰島四種分泌細(xì)胞（細(xì)胞、細(xì)胞、δ細(xì)胞和胰多肽細(xì)胞）都能分泌PTHrP[31]，細(xì)胞能通過激活磷脂酶C和細(xì)胞內(nèi)鈣的明顯升高從而對PTHrP產(chǎn)生反應(yīng)[32]，而且細(xì)胞過表達(dá)PTHrP能促進(jìn)增殖、增加胰島素的分泌、抑制細(xì)胞的凋亡從而導(dǎo)致胰島細(xì)胞的數(shù)量增加、高胰島素血癥和低糖血癥[32-33]。在體外實驗中PTHrP能激活PTH1R的下游通路（具體涉及到PKC-ζ，cyclinE，andcdk2），從而促進(jìn)人細(xì)胞增殖和提高葡萄糖刺激所導(dǎo)致的胰島素分泌[34]。最近在體內(nèi)實驗中每天注射PTHrP（1-36）能促進(jìn)老鼠細(xì)胞和增加葡萄糖耐量[35]。以上實驗證明PTHrP在維持胰島細(xì)胞數(shù)量和治療糖尿病可能是有益的。HHMHHM[36BouvetPTHrPAsPC-1PTHrPMichaelBouvetPTHrP異，從而認(rèn)為PTHrP可能能在胰腺癌動物模型中做為一個有效的腫瘤標(biāo)志物，但PTHrPHHMPTHrPJ21COLO357GSK3PKB/AKTPTHrPPTHrPPTHrPPTHrP在胰腺神經(jīng)內(nèi)分泌腫瘤領(lǐng)域，越來越多的報導(dǎo)證實神經(jīng)內(nèi)分泌腫瘤能分泌PTHrP，并提示神經(jīng)內(nèi)分泌腫瘤伴發(fā)的HHM與之相關(guān)[43-44]，但是仍需要更多的證據(jù)支持。在蛙皮素或酒精導(dǎo)致的急慢性胰腺炎中，PTHrPPTHrPPTHrPHHMPTHrPPTHrPPTHrP腫瘤疾病發(fā)病機(jī)理的認(rèn)識、診斷以及治療方面提供新的途徑。【相關(guān)文獻(xiàn)】報,1998,19(2):197-200.McCauleyLK1,MartinTJ.Twenty-fiveyearsofPTHrPprogress:Fromcancerhormonetomultifunctionalcytokine.JBoneMinerRes,2012,27(6):1231-1239.MoseleyJM,KubotaM,Diefenbach-JaqqerH,etal.Parathyroidhormone-relatedproteinpurifiedfromahumanlungcancercellline.ProcNatlAcadSciUSA,1987,84(14):5048-5052.4BurtisWJ,WuT,BunchC,etal.Identificationofanovel17,000-daltonparathyroidhormone-likeadenylatecyclase-stimulatingproteinfromatumorassociatedwithhumoralhypercalcemiaofmalignancy.JBiolChem,1987,262(15):7151-7156.StrewlerGJ,SternPH,JacobsJW,etal.Parathyroidhormonelikeproteinfromhumanrenalcarcinomacells.Structuralandfunctionalhomologywithparathyroidhormone.JClinInvest,1987,80(6):1803-1807.MartinTJ,MoseleyJM,WilliamsED.Parathyroidhormone-relatedprotein:hormoneandcytokine.JEndocrinol,1997,154(Suppl):S23-S37.VilardagaJP,RomeroG,FriedmanPA,etal.Molecularbasisofparathyroidhormonereceptorsignalingandtrafficking:afamilyBGPCRparadigm.CellMolLifeSci,2011,68(1):1-13.8王錚元,盛湲.甲狀旁腺激素相關(guān)蛋白的研究進(jìn)展.廣東醫(yī)學(xué),2013,34(16):2591-2594.NishiharaM,KanematsuT,TaquchiT,etal.PTHrPandTumorigenesis:IsThereaRoleinPrognosis?AnnNYAcadSci,2007,1117(1):385-392.NakajimaK,TamaiM,OkaniwaS,etal.Humoralhypercalcemiaassociatedwithgastriccarcinomasecretingparathyroidhormone:acasereportandreviewoftheliterature.EndocrJ,2013,60(5):557-562.ItoM,NakashimaM,AlipovGK,etal.Gastriccancerassociatedwithoverexpressionofparathyroidhormone-relatedpeptide(PTHrP)andPTH/PTHrPreceptorinrelationtotumorprogression.JGastroenterol,1997,32(3):396-400.YamashitaS,TakahashiN,HashimotoT,etal.Establishmentandcharacterizationofacellline(IGSK-3)secretinghumanchorionicgonadotropin,adrenocorticotropichormoneandparathyroidhormone-relatedproteinderivedfromprimarypoorlydifferentiatedadenocarcinomaofthestomach.HumCell,2008,21(3):88-94.Yamamura-IdeiY,KitazawaS,KitazawaR,etal.Parathyroidhormone-relatedproteiningastriccancerswithheterotopicossification.Cancer,1993,72(6):1849-1852.AlipovGK,ItoM,NakashimaM,etal.Expressionofparathyroidhormone-relatedpeptide(PTHrP)ingastrictumours.,1997,182(2):174-179.LiuC,Chen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