郭 品 綜述 邱永明 審校

(上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院神經(jīng)外科,上海 200127)

DNA結(jié)合抑制因子(inhibitor of DNA binding,Id)蛋白屬于螺旋 -環(huán) -螺旋(helix-loop-helix,HLH)蛋白超家族,為負(fù)性調(diào)節(jié)因子,缺少基本的 DNA結(jié)合域,無 DNA結(jié)合活性,主要通過螯合廣泛表達(dá),見圖 1。人類的 Id家族包括四名成員,即 Id-1,Id-2,Id-3,Id-4[1],所有的 Id蛋白擁有高度同源的螺旋環(huán)螺旋區(qū)域。經(jīng)過近 20年的研究,它們的細(xì)胞和生物學(xué)特性已逐漸明了。在細(xì)胞分化、凋亡、細(xì)胞周期的調(diào)節(jié)、腫瘤生成、浸潤和轉(zhuǎn)移等不同細(xì)胞生物學(xué)過程中,Id家族各自發(fā)揮不同的生物學(xué)作用[1-3]。Id基因或蛋白的表達(dá)異常,在腫瘤的發(fā)生和發(fā)展過程中起著重要作用。因此,人為調(diào)控 Id基因和蛋白有望成為腫瘤的治療靶點(diǎn)。本文總結(jié)了 Id基因和蛋白在腫瘤發(fā)生發(fā)展以及預(yù)后中的作用,來探討 Id作為腫瘤治療有效治療靶點(diǎn)的可行性。

圖1 Id在 bhlh轉(zhuǎn)錄作用的模型[1]

1 Id在原發(fā)性腫瘤細(xì)胞中的表達(dá)

正常情況下,Id在成熟的成年正常組織中微量表達(dá),而在多個系統(tǒng)的腫瘤中發(fā)現(xiàn) Id的異常表達(dá)[4]。2003年,Lee等[5]在研究肝細(xì)胞癌時發(fā)現(xiàn) Id-1可通過 p16INK4a/RB途徑來影響腫瘤的發(fā)生和發(fā)展。之后,在消化系統(tǒng)的其他腫瘤的研究中也發(fā)現(xiàn)了 Id的異常。如肝細(xì)胞型肝癌中,Id-1在 RNA水平和蛋白水平均存在高表達(dá)[5];在原發(fā)性結(jié)腸癌的研究中,Id-1的表達(dá)水平較正常黏膜相比有所升高[6];另外,Shuno等[7]發(fā)現(xiàn),Id-1和 Id-3的異常表達(dá)與胰腺癌細(xì)胞的轉(zhuǎn)移有關(guān)。

同樣,在生殖系統(tǒng)腫瘤的研究中也發(fā)現(xiàn) Id基因和蛋白的異常。Id-1在卵巢腫瘤、宮頸癌、乳腺癌、子宮內(nèi)膜癌以及前列腺癌中的表達(dá)異常,并且 Id-1的表達(dá)水平與低分化類型、高度的惡性潛能及不良的臨床結(jié)果有關(guān)[8-12];Sablizky等[13]發(fā)現(xiàn)在精原細(xì)胞癌中,Id家族均高表達(dá)。

Id基因和蛋白在中樞神經(jīng)系統(tǒng)腫瘤的研究較少,但也有發(fā)現(xiàn) Id基因和蛋白表達(dá)含量與神經(jīng)系統(tǒng)腫瘤惡性程度的關(guān)系。如在星型細(xì)胞腫瘤中,高級別的腫瘤中 Id1-3的表達(dá)水平高于低級別的腫瘤[14]。目前 Id基因和蛋白表達(dá)含量與神經(jīng)系統(tǒng)腫瘤患者預(yù)后的關(guān)系尚未明確。

2 Id參與腫瘤的發(fā)生發(fā)展

2.1 參與腫瘤血管的生成 血管的生成是腫瘤發(fā)生的關(guān)節(jié)環(huán)節(jié)之一。已證實(shí),Id-1、Id-3和 Id-4在血管生成方面有促進(jìn)作用[15,16]。Si等[17,18]在對胃癌的研究中發(fā)現(xiàn),Id-1的過表達(dá)可使腫瘤血管的密度增加。另外,在口腔鱗狀上皮細(xì)胞癌、卵巢癌、子宮頸癌中,也同樣發(fā)現(xiàn) Id-1的過表達(dá)可能與腫瘤血管的生成有關(guān)[8,19,20],其機(jī)制尚未明確,有研究者推斷可能與 Id-1激活 VEGF有關(guān)。在前列腺癌中,Id-1的過表達(dá)可激活 VEGF,以提供促進(jìn)腫瘤血管生成的自分泌信號[21],從而促進(jìn)腫瘤的發(fā)生發(fā)展。所以作用于 Id-1,以降低 VEGF的活性,干擾腫瘤血管的生成,達(dá)到治療腫瘤的目的。另外,Volpert等[22]發(fā)現(xiàn),Id-1可通過轉(zhuǎn)錄抑制血小板凝血酶敏感蛋白 -1(thrombospondin-1,TSP-1),來調(diào)節(jié)血管的生成。這無疑又證實(shí)了,Id-1可作為腫瘤治療的靶點(diǎn)。

2.2 抑制腫瘤細(xì)胞的凋亡

腫瘤的發(fā)生與細(xì)胞凋亡的調(diào)節(jié)紊亂有密切的關(guān)系。大量的研究證明,Id家族可影響腫瘤細(xì)胞的凋亡。卵巢癌中,Id-1、Id-3蛋白的過表達(dá)可激活 E-box,并且可增加細(xì)胞周期蛋白依賴性激酶抑制劑(Cyclin-dependent kinase inhibitor,CDKI)的表達(dá)水平,抑制抑癌基因的活性,從而抑制細(xì)胞的凋亡[23];在乳腺癌細(xì)胞中,Id-1可通過 P53和NF-kappaB通路來干預(yù)細(xì)胞的凋亡[24];在頭頸鱗狀細(xì)胞癌的研究中,Id-1可通過 NF-kappaB/survivin和 phosphoinositIde 3-kinase/Akt信號途徑阻止腫瘤細(xì)胞的凋亡[25];在腸上皮細(xì)胞中,敲除 Id-1和 Id-2可誘導(dǎo)細(xì)胞的凋亡,而且 Id-2的過表達(dá)可阻止 TGFbeta誘導(dǎo)的凋亡[26];在食管癌中,Id-1可激活 PI3K/Akt/NfkappaB信號通路,抑制細(xì)胞的凋亡,還可抑制 TNF-alpha誘導(dǎo)的細(xì)胞凋亡[27];Koyama等[28]研究稱,在肉瘤細(xì)胞系中,Id-3可增強(qiáng) cddp誘導(dǎo)的細(xì)胞凋亡。

另外,Id-1可降低腫瘤細(xì)胞對化療藥物的敏感性,從而對抗藥物誘導(dǎo)的凋亡。如在膀胱癌中,Id-1的下調(diào)可增強(qiáng)腫瘤細(xì)胞對表柔比星的敏感性,誘導(dǎo)細(xì)胞凋亡[29];Wong等研究稱,在前列腺癌細(xì)胞系DU145、PC3中,利用 siRNA技術(shù)檢測到 Id-1的下調(diào),可增加癌細(xì)胞對紫杉醇的敏感性,從而促進(jìn)細(xì)胞凋亡[30],其抗藥性可能通過 AkT途徑來發(fā)揮作用[31];鼻咽癌細(xì)胞中,Id-1可通過 Raf/MEK通路阻止紫杉醇誘導(dǎo)的細(xì)胞凋亡[32]。

由此,我們可以把 Id基因和蛋白作為腫瘤治療靶點(diǎn),促進(jìn)腫瘤細(xì)胞的凋亡,從而達(dá)到治療腫瘤的目的。

2.3 調(diào)節(jié)腫瘤細(xì)胞的分化

細(xì)胞分化是細(xì)胞之間產(chǎn)生差異的過程,細(xì)胞的非正常分化,常使得正常細(xì)胞瘤變。宮頸癌細(xì)胞中,Id-1的過表達(dá)可影響細(xì)胞分化,從而加速腫瘤的惡性進(jìn)程[9]。前列腺癌細(xì)胞通過 Id-1調(diào)節(jié)破骨細(xì)胞的分化,間接作用于前列腺癌骨轉(zhuǎn)移[33]。在肝臟腫瘤的研究中,Id-1可調(diào)節(jié)肝細(xì)胞瘤細(xì)胞的分化,從而加速肝細(xì)胞癌變的進(jìn)程[34]。Kebebew等[35]發(fā)現(xiàn),Id-1基因的過表達(dá)可調(diào)節(jié)甲狀腺癌細(xì)胞的分化。Id-2在腫瘤的研究較少,但也發(fā)現(xiàn),Id-2可調(diào)節(jié)乳腺上皮細(xì)胞的、肝星形細(xì)胞、人類角質(zhì)化細(xì)胞的分化,調(diào)控 Id2的表達(dá)量,可阻止這些細(xì)胞的非正常分化[36-38]。另外,Umetani等[39]發(fā)現(xiàn),Id-4的失活,可與結(jié)直腸癌細(xì)胞的低分化有關(guān)。

可見 Id基因和蛋白在細(xì)胞分化中的重要作用,認(rèn)為調(diào)節(jié) Id基因和蛋白的含量,可影響腫瘤細(xì)胞的分化,為腫瘤的治療提供新的思路。

3 Id與腫瘤患者預(yù)后的關(guān)系

Id的表達(dá)的高低,可影響患者的預(yù)后。Ding等[40]發(fā)現(xiàn),在乙肝型肝細(xì)胞癌患者中,Id-1過表達(dá)患者較 Id-1低者的生存時間短,其原因可能與 Id-1的過表達(dá)與腫瘤的級別高有關(guān),所以 Id-1可能作為乙肝型肝細(xì)胞癌患者預(yù)后預(yù)測的指標(biāo)。Tang等[41]在對急性淋巴細(xì)胞性白血病患者的研究中發(fā)現(xiàn),Id-1高表達(dá)的患者的預(yù)后普遍較 Id-1低者差,所以 Tang提出 Id-1可作為急性淋巴細(xì)胞性白血病靶向治療的靶點(diǎn)。在對 Id-2的研究中,也發(fā)現(xiàn) Id-2可影響患者的預(yù)后,如 Stighall等[42]發(fā)現(xiàn)在原發(fā)性乳腺癌患者中,Id-2高表達(dá)患者的預(yù)后較好,并且有研究證實(shí),在食管上皮細(xì)胞癌中,胞漿和胞核均存在 Id-2高表達(dá)的患者生存時間較長[43],所以 Id-2也可作為判斷預(yù)后的一個獨(dú)立指標(biāo)。Umetani等[39]在研究結(jié)直腸癌時發(fā)現(xiàn),Id-4可作為抑癌基因,從而影響患者的預(yù)后。

由此可見,Id可作為影響和判斷預(yù)后的潛在的標(biāo)志。這也為我們探討 Id作為腫瘤治療的靶點(diǎn)提供了又一有力的證據(jù)。

綜上所述,Id在腫瘤的發(fā)生、發(fā)展及對患者預(yù)后發(fā)揮重要作用。腫瘤的治療,可考慮從控制 Id基因和蛋白表達(dá)水平入手,特別是 Id-1。Id作為高效性和選擇性治療癌癥的靶點(diǎn),有以下原因:①Id蛋白已被證明調(diào)解的幾個重要基因的活性調(diào)控腫瘤的生成和癌癥進(jìn)展[1]。Id蛋白作為調(diào)控血管生成、增殖、分化、遷移、侵襲和細(xì)胞間相互作用的通路的核心之一。因此,以 Id作為目標(biāo)可能會同時影響癌癥的發(fā)展幾個不同的方面,可能實(shí)現(xiàn)高功效;②Id蛋白在大部分成人的成熟組織中尚未表達(dá)[4]。這可能是一種全身治療的優(yōu)勢,因?yàn)榇蠖鄶?shù)正常細(xì)胞的功能不會受到影響,從而有可能實(shí)現(xiàn)目標(biāo)的選擇性和低毒性。③Id可影響患者預(yù)后,認(rèn)為調(diào)控 Id的含量,可延長患者的生存期限。

4 展 望

Id的異常表達(dá)可能是一種癌基因的上游或腫瘤抑制基因失調(diào)的結(jié)果,目前的研究只是停留在推測階段,其在腫瘤發(fā)生發(fā)展及預(yù)后的作用機(jī)制還需要更多的證據(jù)支持。每一種靶點(diǎn)的選擇都有潛在的優(yōu)點(diǎn)或者缺點(diǎn),其可行性和有效性還都需要大量的證據(jù)支持。相信隨著人類對 Id基因和蛋白越來越多的了解,其作為腫瘤治療靶點(diǎn)的可行性會得到進(jìn)一步的證實(shí)。接下來,需要的是更深入的研究和更充分的臨床證據(jù)。

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