朱明月，李孟森，3

（1.海南省腫瘤發(fā)生和干預(yù)重點(diǎn)實(shí)驗(yàn)室，海南海口571199；2.海南醫(yī)學(xué)院分子生物學(xué)重點(diǎn)實(shí)驗(yàn)室，海南?？?71199；3.海南醫(yī)學(xué)院腫瘤研究所，海南?？?71100）

·述評·

甲胎蛋白：治療肝癌的新靶點(diǎn)

朱明月1，2，李孟森1，2，3

（1.海南省腫瘤發(fā)生和干預(yù)重點(diǎn)實(shí)驗(yàn)室，海南海口571199；2.海南醫(yī)學(xué)院分子生物學(xué)重點(diǎn)實(shí)驗(yàn)室，海南?？?71199；3.海南醫(yī)學(xué)院腫瘤研究所，海南?？?71100）

甲胎蛋白(Alpha fetoprotein，AFP)在肝癌發(fā)生過程中所起的生物學(xué)作用一直是個(gè)謎。由于其是肝癌細(xì)胞高特異性表達(dá)的蛋白質(zhì)，臨床上作為診斷肝癌的金標(biāo)準(zhǔn)，但是AFP在肝癌發(fā)生過程有何功能并不清楚。最近我們的研究發(fā)現(xiàn)，AFP具有信息調(diào)控分子樣作用，AFP不僅能與維甲酸受體-β(RAR-β)結(jié)合，阻遏RAR-β進(jìn)入細(xì)胞核內(nèi)調(diào)節(jié)靶基因的表達(dá)，同時(shí)也能抑制Caspase-3的活性，阻斷凋亡信號的傳遞，更重要的是AFP激活PI3/AKT等生長信號途徑，提示AFP具有抗凋亡誘導(dǎo)的功能，靶向抑制AFP表達(dá)能增加肝癌細(xì)胞對腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(TRAIL)和全反式維甲酸(ATRA)的敏感性，新發(fā)現(xiàn)AFP的這些功能，預(yù)示它是肝癌細(xì)胞耐藥的新靶點(diǎn)，為肝癌的生物治療提供新的思路和策略。

甲胎蛋白；肝癌；治療；新靶點(diǎn)

肝細(xì)胞癌(Hepatocellular carcinoma，HCC)是嚴(yán)重威脅人類健康的重大疾病，是癌癥發(fā)病譜中最常見的癌癥類型之一，在全球范圍內(nèi)腫瘤相關(guān)性死亡因素中排名第三，全球每年有超過60萬新發(fā)病例。肝癌的發(fā)生與肝炎病毒感染密切相關(guān)，由于我國是肝炎病毒感染的高發(fā)國家，因而我國肝癌發(fā)病率遠(yuǎn)高于世界平均水平，我國每年約有11萬人死于肝癌[1]。由于肝癌發(fā)生過程有很大的隱蔽性，且有易發(fā)生早期轉(zhuǎn)移、浸潤至鄰近及更遠(yuǎn)組織的傾向，所以肝癌的預(yù)防和治療是世界性醫(yī)學(xué)難題，至今仍缺乏有效防治手段。因而預(yù)警肝癌發(fā)生以及肝癌發(fā)病機(jī)制的研究受到國內(nèi)外醫(yī)學(xué)界和生命科學(xué)界的廣泛關(guān)注。由于甲胎蛋白(Alpha fetoprotein，AFP)是目前臨床上用于診斷肝癌的高特異性標(biāo)志物，所以近期對AFP在肝癌發(fā)生過程發(fā)揮的作用進(jìn)行一系列研究，試圖探索AFP在肝細(xì)胞惡性轉(zhuǎn)化、肝癌細(xì)胞增殖和調(diào)控過程中的作用機(jī)制，對重新認(rèn)識AFP的生物學(xué)功能及其在肝癌靶向治療的價(jià)值有重要的科學(xué)意義。

1 AFP在乙型肝炎病毒誘導(dǎo)肝細(xì)胞惡性轉(zhuǎn)化過程的作用

肝細(xì)胞感染乙型肝炎病毒(Hepatitis B virus，HBV)是誘發(fā)肝癌的重要因素，80%以上的肝癌發(fā)生與感染HBV或丙型肝炎病毒有關(guān)[2]。盡管HBV沒有直接誘導(dǎo)肝細(xì)胞惡性轉(zhuǎn)化的功能[3-4]，但是HBV的x蛋白(HBx)則能通過調(diào)節(jié)細(xì)胞內(nèi)的信號傳遞，包括激活PI3K/AKT信號，促進(jìn)肝細(xì)胞的惡性轉(zhuǎn)化[5-6]、癌細(xì)胞的增殖和癌細(xì)胞的增殖[7]，并且有誘導(dǎo)肝癌血管生成和促進(jìn)癌細(xì)胞轉(zhuǎn)移的作用[8]。AFP是肝癌細(xì)胞合成的高特異性蛋白質(zhì)，許多肝癌患者(70%～80%)在發(fā)病期間都有AFP基因高表達(dá)的特征。AFP是一種胚原蛋白，其基因在胎兒發(fā)育過程開放表達(dá)，而在人出生兩年后基本處于關(guān)閉狀態(tài)，但是在成年人肝細(xì)胞惡性轉(zhuǎn)化的早期，肝細(xì)胞內(nèi)的AFP基因重新被激活而大量表達(dá)，所以在臨床上，AFP被用作診斷肝癌的經(jīng)典腫瘤標(biāo)記物和金標(biāo)準(zhǔn)，但是，肝癌細(xì)胞分泌的AFP在肝癌發(fā)生過程中發(fā)揮何種作用并不清楚。大量研究[9-12]發(fā)現(xiàn)，AFP具有刺激肝癌細(xì)胞增殖的功能，近期我們研究[13]發(fā)現(xiàn)，AFP具有激活PI3K/AKT信號的功能，通過該信號途徑誘導(dǎo)癌基因的表達(dá)，促進(jìn)肝癌細(xì)胞增殖，這些研究結(jié)果提示，AFP具有誘導(dǎo)肝癌細(xì)胞增殖的生物學(xué)功能。然而在肝細(xì)胞感染乙型肝炎病毒后是否通過激活A(yù)FP基因表達(dá)，驅(qū)動肝細(xì)胞惡性轉(zhuǎn)化？因?yàn)锳FP表達(dá)是肝細(xì)胞惡性轉(zhuǎn)化過程的早期事件，暗示AFP基因表達(dá)可能與肝細(xì)胞惡性轉(zhuǎn)化密切相關(guān)。有研究表明，HBx能通過抑制p53對AFP基因的阻遏作用，導(dǎo)致AFP基因被激活而表達(dá)[14-15]，由于HBx具有激活PI3K/AKT信號傳遞誘導(dǎo)肝癌發(fā)生的功能[16-17]，所以可以確定，PI3K/AKT活化與HBx誘導(dǎo)肝癌發(fā)生密切相關(guān)，但是HBx如何激活PI3K/AKT信號并不清楚。近期我們用載體的肝癌標(biāo)本以及體外細(xì)胞研究HBx在誘導(dǎo)肝細(xì)胞惡性轉(zhuǎn)化過程和AFP發(fā)揮的作用，研究結(jié)果表明，在HBx誘導(dǎo)肝細(xì)胞惡性轉(zhuǎn)化的進(jìn)程中，AFP優(yōu)先于其他癌基因如Src、Ras等基因的表達(dá)，進(jìn)一步研究發(fā)現(xiàn)，AFP能激活PI3K/AKT信號，通過該信號促進(jìn)Src、Ras蛋白的合成[18]，這些研究結(jié)果，提供一條清晰的信息調(diào)節(jié)通路：HBx抑制p53對AFP啟動子的阻遏活性→AFP表達(dá)升高→激活PI3K/AKT信號→誘導(dǎo)Src、Ras等基因的表達(dá)→促進(jìn)肝細(xì)胞惡性轉(zhuǎn)化。因此，HBx對AFP表達(dá)的優(yōu)先選擇性具有間接激活PI3K/AKT的作用，這是HBx誘導(dǎo)肝癌發(fā)生的重要環(huán)節(jié)，解釋了臨床上早期肝癌患者檢測到AFP以及AFP作為肝癌特異性標(biāo)志物的內(nèi)在機(jī)制。

2 AFP調(diào)控肝癌細(xì)胞增殖和抗凋亡作用

AFP是肝癌細(xì)胞表達(dá)的高特異性蛋白質(zhì)，肝炎病毒是誘發(fā)肝癌的關(guān)鍵生物因素，在活動性肝炎或肝硬化后期，血清中可檢驗(yàn)出高含量的AFP存在，這是肝細(xì)胞向肝癌轉(zhuǎn)化的重要標(biāo)志。一些研究[19-23]發(fā)現(xiàn)AFP在腫瘤發(fā)生過程中所起的作用，表現(xiàn)出“雙向性”，對于乳腺癌細(xì)胞，其有抑制癌細(xì)胞增殖作用，但是AFP基因的轉(zhuǎn)錄抑制因子ATBF1A的高表達(dá)能增加乳腺癌患者向好的預(yù)后效果[24]；對于消化道腫瘤，AFP的表達(dá)與腫瘤的增殖和轉(zhuǎn)移密切相關(guān)，近期研究[25-28]發(fā)現(xiàn)AFP能促進(jìn)胃癌細(xì)胞的增殖和轉(zhuǎn)移；對于肝癌，早期研究已經(jīng)發(fā)現(xiàn)AFP具有促進(jìn)肝癌細(xì)胞增殖的生物學(xué)功能[9-10]，近期Hung等[29]用66例肝癌患者的癌組織和其配對的肝組織為對象，采用蛋白質(zhì)雜交和免疫組化方法觀察發(fā)現(xiàn)，抑制AFP表達(dá)的轉(zhuǎn)錄調(diào)節(jié)因子LHX4在癌組織表達(dá)明顯降低，提示AFP的高表達(dá)具有促進(jìn)肝癌發(fā)生的生物學(xué)作用，而且Ho等[30]研究發(fā)現(xiàn)纖維細(xì)胞生長因子受體-4通過其介導(dǎo)的信號促進(jìn)AFP表達(dá)從而驅(qū)動肝癌發(fā)生的進(jìn)程；動物實(shí)驗(yàn)也證明抑制AFP的表達(dá)能有效的誘導(dǎo)肝癌細(xì)胞在體內(nèi)的凋亡[31]。有研究[11,32]結(jié)果也表明，AFP與其受體結(jié)合，通過激活Ca2+信號途徑，促進(jìn)癌基因c-fos,c-jun、ras等基因的表達(dá)，刺激肝癌細(xì)胞生長。這些研究結(jié)果表明，AFP在肝癌的發(fā)生過程中具有促進(jìn)癌細(xì)胞增殖作用，提示AFP有抗凋亡誘導(dǎo)的生物學(xué)功能。

3 AFP作為治療肝癌生物治療的新靶點(diǎn)

盡管AFP能促進(jìn)肝癌細(xì)胞增殖，但是AFP通過何種機(jī)制促進(jìn)肝癌細(xì)胞增殖并不清楚，而且AFP是否通過促增殖的方式對抗凋亡誘導(dǎo)？研究[33]已經(jīng)發(fā)現(xiàn)，肝癌細(xì)胞不僅能抵抗體內(nèi)分泌的腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(TRAIL)等細(xì)胞因子誘導(dǎo)的凋亡，而且也有耐受化學(xué)藥物毒性的特性[34]，但是肝癌細(xì)胞內(nèi)哪些因子在肝癌耐藥過程中發(fā)揮重要作用，是研究生物治療肝癌的重大問題。Tang等[35-36]研究發(fā)現(xiàn)靶向抑制AFP表達(dá)，能阻止肝癌細(xì)胞的增殖并能誘導(dǎo)肝癌細(xì)胞凋亡。AFP是肝癌細(xì)胞分泌的高特異性蛋白，我們推測，在肝癌的發(fā)生過程中，癌細(xì)胞高表達(dá)的AFP不僅僅作為一個(gè)標(biāo)志物，而是具有調(diào)控細(xì)胞生長的物質(zhì)，因?yàn)榘凑占?xì)胞高度利用蛋白質(zhì)特性，其不可能合成一種沒有生物活性的蛋白質(zhì)，所以肝癌細(xì)胞表達(dá)AFP在細(xì)胞內(nèi)外必定有未曾發(fā)現(xiàn)的生物學(xué)功能。我們近期已經(jīng)發(fā)現(xiàn)在人肝癌細(xì)胞[11]、人子宮頸癌細(xì)胞[37]、NIH3T3細(xì)胞[38]膜表面存在不同親和常數(shù)的受體，既然有受體的存在，就有其調(diào)節(jié)細(xì)胞生長活性的存在。有研究[11,37]發(fā)現(xiàn)，AFP與細(xì)胞膜受體結(jié)合后能通過影響細(xì)胞內(nèi)的第二信息物質(zhì)cAMP和Ca2+等的濃度，從而調(diào)控轉(zhuǎn)錄調(diào)節(jié)因子的作用，影響癌基因的表達(dá)；盡管有些肝癌患者的血清檢測AFP的含量是陰性，但是，并不是這些患者的肝癌細(xì)胞不合成AFP，而是合成的AFP并不分泌到血液緣故，這些在細(xì)胞內(nèi)的AFP同樣發(fā)揮抗凋亡作用。研究[39]發(fā)現(xiàn)，肝癌細(xì)胞內(nèi)的AFP選擇性與促進(jìn)凋亡信號的關(guān)鍵物質(zhì)Caspase-3結(jié)合，抑制TRAIL受體介導(dǎo)的信號傳遞，而且AFP還具有抑制全反式維甲酸受體(ATRA)-β(RAR-β)的功能，阻止RAR-β向胞核轉(zhuǎn)移，抑制其轉(zhuǎn)錄功能，而RAR-β是一個(gè)重要的腫瘤抑制因子，其能抑制Survivin等基因的表達(dá)，所以AFP也能通過抑制RAR-β的作用[40]；近期研究發(fā)現(xiàn)，AFP通過抑制RAR-β導(dǎo)致GADD153表達(dá)下降[41]，以及Fn14表達(dá)升高[42]，因?yàn)镚ADD153是誘導(dǎo)腫瘤細(xì)胞凋亡的細(xì)胞因子，而Fn14則是促進(jìn)腫瘤細(xì)胞增殖蛋白，也就是AFP不僅影響凋亡信號的傳遞，同時(shí)也能影響凋亡相關(guān)基因的表達(dá)，通過這些方式增加肝癌細(xì)胞抵抗ATRA的作用；近期有研究[13,43,44]也發(fā)現(xiàn)，AFP能與PTEN結(jié)合，通過抑制PTEN的酶活性，激活肝癌細(xì)胞內(nèi)磷酯酰肌醇-3激酶(PI3K)和蛋白激酶B(AKT)活性，通過激活PI3K/AKT信號途徑促使肝癌細(xì)胞耐受凋亡的誘導(dǎo)。這些研究結(jié)果提示，AFP是肝癌細(xì)胞耐受凋亡誘導(dǎo)的一個(gè)關(guān)鍵的靶分子，AFP在細(xì)胞外，不僅通過與其受體的作用，激活生長信號的傳遞，而且AFP在細(xì)胞內(nèi)也能通過抑制凋亡信號的轉(zhuǎn)導(dǎo)和激活生長信號的傳遞，促使肝癌細(xì)胞耐受化學(xué)藥物和生物藥物誘導(dǎo)的凋亡。所以，AFP的抗凋亡作用不僅通過促增殖而且也能通過抑制凋亡信號以及激活生長信號的作用對抗體內(nèi)細(xì)胞因子、化學(xué)藥物誘導(dǎo)凋亡。這些研究逐步揭示了甲胎蛋白所隱藏的生物學(xué)功能及其作用機(jī)制，這是AFP具有信息調(diào)節(jié)分子樣作用和作為靶分子治療肝癌的新發(fā)現(xiàn)，為肝癌的生物治療提供新的策略，也將為肝癌的藥物治療帶來新希望。

4 AFP作為靶向治療肝癌的展望

目前，AFP在肝癌的發(fā)生和抗凋亡過程中的作用機(jī)制并沒有完全清楚，當(dāng)前的研究結(jié)果已經(jīng)顯示，AFP在肝癌的發(fā)生過程中發(fā)揮關(guān)鍵性作用，而且其已經(jīng)是醫(yī)學(xué)界公認(rèn)的為數(shù)不多的高特異性腫瘤標(biāo)志物，其生物學(xué)功能得到廣泛的關(guān)注。由于AFP基因在肝癌的演進(jìn)過程并未發(fā)現(xiàn)與耐藥相關(guān)的任何突變，而是基因表達(dá)發(fā)生改變，特別是在肝炎病毒的迫脅下其基因如何從關(guān)閉到開放的表觀遺傳修飾改變，不同于突變，表觀遺傳改變是細(xì)胞快速應(yīng)對環(huán)境變化的重要機(jī)制。因此研究AFP基因以及其翻譯后的表觀遺傳修飾改變是探索AFP功能的關(guān)鍵問題，也是探索AFP作為治療肝癌新靶點(diǎn)的核心問題。深入研究AFP基因表觀遺傳學(xué)的改變，不僅能闡明AFP在病毒性肝癌發(fā)生過程的作用機(jī)制，而且能揭示AFP所隱藏的生物學(xué)功能，對認(rèn)識肝癌發(fā)生、轉(zhuǎn)移、耐藥和靶向生物治療有非常重要的臨床意義。

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Novel function of alpha fetoprotein:A drug therapeutical target of hepatocellular carcinoma.

ZHU Ming-yue1,2, LI Meng-sen1,2,3.1.Hainan Provincial Key Laboratory of Carcinogenesis and Intervention,Haikou,Hainan Province, 571199;2.Key Laboratory of Molecular Biology of Hainan Medical College,Haikou,Hainan Province,571199;3.Tumor Institution of Hainan Medical College,Haikou,Hainan Province,571100

Alpha-fetoprotein(AFP)associated with the development of hepatocellular carcinomas(HCC). AFP was applied to as a golden tumor marker for diagnosing HCC due to AFP gene was activated in early stage of malignant transformation of liver cell.However,the molecular mechanisms that the role of AFP on hepatocarcinogenesis remain poorly understood.Recently,we found that AFP not only exerted role on impeding all trans retinoid acid receptor-b(RAR-b)regulated expression of target genes,but also blocked transduction of apoptotic signal through suppressing the activity of caspase-3;Importantly,AFP has a function to activate phosphoinositide-3-kinase(PI3K)/protein kinase B(AKT)signal transduction via inhibiting activity of PTEN.These datum implied that AFP plays critical role on anti-apoptosis of HCC.AFP Inhibited expression of AFP was able to augment HCC sensitivity to tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and all trans retinoid acid.These datum evidenced that AFP has a function for driving malignant transformation of liver cells and antagonizing apoptotic induced by agents of HCC.Revealed novel function of AFP foreshowed that AFP maybe play a pioneer factor role on driving malignant transformation of liver cells,andAFP was used as a gene target for therapy of HCC.

Alpha fetoprotein(AFP);Malignant transformation of liver cells;apoptosis;Therapy of hepatocellular carcinoma.

R735.7

A

1003—6350（2014）01—0001—04

10.3969/j.issn.1003-6350.2014.01.0001

2013-11-10)

國家自然科學(xué)基金(編號：81260306，81160261，31060164，30960153)；教育部新世紀(jì)優(yōu)秀人才支持計(jì)劃(編號：NCET-10-0124)；教育部科學(xué)技術(shù)研究重點(diǎn)項(xiàng)目(編號：211146)；海南省重點(diǎn)科技項(xiàng)目(編號：DZXM20110038)；海南省自然科學(xué)基金(編號：309034，310044)資助。

李孟森。E-mail：mengsenli@163.com