何淑英 白 嵐

甲狀旁腺激素相關(guān)蛋白與消化系腫瘤的關(guān)系

何淑英1白 嵐2

甲狀旁腺激素相關(guān)蛋白（PTH rP）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。

甲狀旁腺激素相關(guān)蛋白；惡性腫瘤；消化系統(tǒng)

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(shí)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，PTH rP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。

一、PTHrP與胃癌

胃癌患者伴發(fā)高鈣血癥（HHM）的報(bào)導(dǎo)逐漸增多，通過免疫組織化學(xué)和免疫放射分析技術(shù)，發(fā)現(xiàn)這些患者的癌組織表達(dá)PTHrP和PTH1R，而且外周血中PTHrP的表達(dá)水平也升高[10-11]，同時(shí)日本學(xué)者從低分化胃腺癌組織中分離建立的細(xì)胞系IGSK-3，運(yùn)用免疫細(xì)胞化學(xué)法也證明該細(xì)胞系能分泌PTHrP[12]，以上證據(jù)表明PTHrP在胃癌組織中普遍表達(dá)。因PTHrP與HHM有關(guān)，最初報(bào)導(dǎo)PTHrP在胃癌患者中能促進(jìn)異位骨化[13]，進(jìn)而有研究表明低分化胃癌PTHrP陽性率能達(dá)到100%，中分化為95.5%，低分化只有45%，同時(shí)發(fā)現(xiàn)癌組織侵潤較深的部位較黏膜癌PTH rP表達(dá)更為明顯，從而認(rèn)為胃癌PTHrP過表達(dá)與腫瘤組織進(jìn)展及惡性轉(zhuǎn)化有關(guān)，體外實(shí)驗(yàn)證明分化好的胃癌細(xì)胞株并不會(huì)表達(dá)PTHrP，然而低分化的胃癌細(xì)胞株高表達(dá)PTHrP[14]。Cuiping Liu等研究進(jìn)一步把PTHrP在人胃黏膜組織的表達(dá)定位于腸嗜鉻樣細(xì)胞（ECL cells）[15]。但目前除了有關(guān)內(nèi)切蛋白酶-弗林蛋白酶（Furin）和PTH rP能形成正反饋從而促進(jìn)胃癌細(xì)胞株增殖的報(bào)導(dǎo)外[16]，關(guān)于PTHrP與胃癌關(guān)系的其他機(jī)制的報(bào)導(dǎo)還沒有發(fā)現(xiàn)。我國關(guān)于胃癌與PTHrP之間關(guān)系的研究還未見大樣本的臨床資料，所以在我國需要進(jìn)一步的臨床資料以證明PTHrP與胃癌的相關(guān)性，同時(shí)PTHrP與胃癌患者的分期及轉(zhuǎn)移之間的關(guān)系及機(jī)制也需要進(jìn)一步明確。

二、PTHrP與大腸癌

已經(jīng)有文獻(xiàn)報(bào)道在大腸腺瘤和癌周正常的黏膜上皮中沒有檢測到PTHrP，而在大腸腺癌PTHrP陽性率達(dá)到94.4%，與分化良好的腺癌比較低分化腺癌PTHrP表達(dá)更為明顯，同時(shí)發(fā)現(xiàn)PTHrP與大腸癌浸潤深度、脈管侵犯、淋巴結(jié)轉(zhuǎn)移、肝轉(zhuǎn)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]。JA Carron1等證明PTHrP和PTH1R共表達(dá)于結(jié)腸癌組織[18]。X iaoli Shen等體外實(shí)驗(yàn)證明過表達(dá)PTHrP能促進(jìn)結(jié)腸癌株Lovo增殖，增加細(xì)胞對細(xì)胞外基質(zhì)的粘連和提高整合蛋白的表達(dá)[19]。隨后體內(nèi)實(shí)驗(yàn)進(jìn)一步研究證明過表達(dá)PTHrP能抑制細(xì)胞凋亡、促進(jìn)細(xì)胞侵襲和遷徙，而且通過體內(nèi)、體外實(shí)驗(yàn)發(fā)現(xiàn)AKT的激活和糖原合成酶3的活性降低與之有關(guān)[20-21]，在此基礎(chǔ)上Ramanjaneya V.Mula等進(jìn)一步證明PTHrP激活A(yù)KT的具體機(jī)制是通過激活Rac1，進(jìn)而導(dǎo)致整合蛋白6 4的增加，而Rac1的激活是Rac-specific鳥嘌呤核苷酸交換因子Tiam1活化的結(jié)果[22]。以上實(shí)驗(yàn)結(jié)果同時(shí)在裸鼠的異體移植瘤生長實(shí)驗(yàn)中得到了驗(yàn)證[21]。M aría Julia Martín等進(jìn)一步拓展了PTHrP促進(jìn)結(jié)腸癌細(xì)胞增殖的通路，包括ERK1/2，αp38 MAPK，and PI3K通路[22]。針對PTHrP在結(jié)腸癌發(fā)揮作用的機(jī)制，Bhatia等證明PTH rP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）上發(fā)現(xiàn)PTHrP在轉(zhuǎn)錄水平上能導(dǎo)致整合蛋白亞基5和1的過表達(dá)，而且能通過沉默PTHrP所逆轉(zhuǎn)，但是起直接或間接作用的蛋白和整合蛋白的啟動(dòng)序列仍有待確定[24]。因此針對PTHrP的表達(dá)和胞分泌信號通路可能是一個(gè)控制結(jié)腸癌細(xì)胞生長、侵襲和遷徙的有效工具。

三、PTHrP與肝癌

早期Roskams T等通過運(yùn)用免疫組織化學(xué)的方法研究24例原發(fā)性肝癌和22例腺癌肝轉(zhuǎn)移，發(fā)現(xiàn)在膽管細(xì)胞型肝癌中PTHrP陽性率為100%，而肝細(xì)胞型肝癌和轉(zhuǎn)移型肝癌中PTHrP表達(dá)為陰性，在混合型肝癌中PTHrP只在膽管細(xì)胞星區(qū)域表達(dá)陽性，從而認(rèn)為PTHrP是診斷肝癌類型和肝轉(zhuǎn)移的一個(gè)有用指標(biāo)[25]。但是臨床觀察肝細(xì)胞癌伴HHM大約占患者總數(shù)的4.5%，肝內(nèi)膽管癌伴發(fā)HHM更少，同時(shí)通過文獻(xiàn)查閱，只有2例文獻(xiàn)報(bào)道混合型肝細(xì)胞癌和膽管細(xì)胞癌伴發(fā)HHM[26]，而原發(fā)于肝臟的鱗癌伴發(fā)HHM并能分泌PTHrP的報(bào)導(dǎo)也有少數(shù)[27]。以上臨床資料說明PTH rP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，LinW ang等通過理論上分析認(rèn)為活化PTH rP能耦合G蛋白受體從而增加肝癌細(xì)胞的粘連性，進(jìn)而促進(jìn)肝癌細(xì)胞侵襲和遷徙[28]。另外，TGF-β在肝細(xì)胞中能刺激PTHrP的分泌，并且進(jìn)一步驗(yàn)證了PTH rP是TGF-β抑制肝細(xì)胞增殖的下游調(diào)控點(diǎn)[29]。此外，Yanna Cao等體內(nèi)實(shí)驗(yàn)證明在肝癌細(xì)胞株Hep3B和HuH-7上PTHrP是TGF-β促凋亡的一個(gè)有效調(diào)控點(diǎn)[30]。上述實(shí)驗(yàn)證實(shí)PTHrP能促進(jìn)肝癌的發(fā)展，但是也有研究得出相反的結(jié)果，LiH等研究認(rèn)為高度分化的肝癌株HepG2能分泌PTHrP和PTH1R，而且PTHrP能作為自分泌或旁分泌生長因子抑制HepG2的生長[29]。綜上所述，目前對肝癌的研究較少，PTHrP與肝癌的分化、轉(zhuǎn)移、診斷等是否有關(guān)，需要更大臨床樣本證實(shí)，其中所牽涉到的機(jī)制需要更多的證據(jù)。

四、PTH rP與胰腺癌

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PTH rP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(shí)驗(yàn)中PTHrP能激活PTH1R的下游通路（具體涉及到PKC-ζ，cyclin E，and cdk2），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(shí)驗(yàn)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(shí)驗(yàn)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。

在胰腺癌中，內(nèi)分泌型胰腺癌伴發(fā)HHM比外分泌型胰腺癌更常見，明確由PTHrP引起的HHM更加少見[36]，但是Bouvet等通過體內(nèi)實(shí)驗(yàn)證實(shí)PTHrP在胰腺腺癌中普遍表達(dá)并且能促進(jìn)胰腺癌細(xì)胞株AsPC-1增殖，體外證實(shí)PTHrP在細(xì)胞質(zhì)和細(xì)胞核中均有表達(dá)[37]，隨后M ichael Bouvet等在體外實(shí)驗(yàn)中運(yùn)用裸鼠的異體移植瘤方法發(fā)現(xiàn)對照組和實(shí)驗(yàn)組血清和組織中的PTHrP表達(dá)存在明顯差異，從而認(rèn)為PTHrP可能能在胰腺癌動(dòng)物模型中做為一個(gè)有效的腫瘤標(biāo)志物，但同時(shí)也指出，在證實(shí)PTHrP在患者中是一個(gè)有效提示胰腺癌的指標(biāo)需結(jié)合腫瘤分期、預(yù)后、腫瘤類型等[38]。除此之外也有文獻(xiàn)提示HHM和PTHrP結(jié)合起來可以作為胰腺癌轉(zhuǎn)移的早期標(biāo)志物[39]。John J等證實(shí)了21整合蛋白在快速生長胰腺癌細(xì)胞株COLO 357中通過GSK3和PKB/AKT通路負(fù)反饋調(diào)節(jié)PTHrP并促進(jìn)細(xì)胞遷移[40-42]。雖然PTHrP促胰腺癌發(fā)展的機(jī)制已有一定的了解，但是因?yàn)橐认侔┌l(fā)病率低，迄今為止沒有大樣本病例資料來來明確胰腺癌與PTH rP之間的關(guān)系，從而限制了PTHrP在胰腺癌中的應(yīng)用。

在胰腺神經(jīng)內(nèi)分泌腫瘤領(lǐng)域，越來越多的報(bào)導(dǎo)證實(shí)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，PTHrP的表達(dá)水平均明顯升高，而且在急慢性胰腺炎疾病進(jìn)展中有研究提示PTH rP參與炎癥及胰腺纖維化的過程[45-46]，但具體機(jī)制尚不明確。

五、展望

PTHrP從最初單一的認(rèn)為是引起惡性腫瘤患者HHM的主要原因，到現(xiàn)在認(rèn)為的多功能細(xì)胞因子，其生物效應(yīng)極為復(fù)雜，迄今為止其在惡性腫瘤骨轉(zhuǎn)移的溶骨性改變、胚胎發(fā)育以及心血管發(fā)育和血壓調(diào)節(jié)方面的作用機(jī)制研究比較明確。雖然諸多證據(jù)提示PTHrP與消化系腫瘤的分化、進(jìn)展、預(yù)后等相關(guān)，但PTHrP在不同消化系腫瘤中的作用還沒有完全的定論。相信隨著對PTHrP不同水平調(diào)控機(jī)制認(rèn)識的深入，它在消化系腫瘤中多種重要的生物學(xué)功能將進(jìn)一步明確，從而為臨床消化系腫瘤疾病發(fā)病機(jī)理的認(rèn)識、診斷以及治療方面提供新的途徑。

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2014-12-24）

（本文編輯：何美蓉）

10.3969/j.issn.1672-2159.2015.01.032

510515南方醫(yī)科大學(xué)南方醫(yī)院1消化內(nèi)科；2惠僑科

白嵐，E-mail：bailan1963@126.com

國家自然科學(xué)基金（81170354）