引用本文
孙栋勋（综述）, 蔡志毅（审校）. EGFR/PI3K/Akt细胞信号传导通路与肿瘤. 检验医学,2014, 29(7): 768-773[SUN Dongxun, CAI Zhiyi. EGFR/PI3K/Akt signaling pathway with tumor. Labratory Medicine, 2014, 29(7): 768-773]  
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EGFR/PI3K/Akt细胞信号传导通路与肿瘤
孙栋勋（综述）1, 蔡志毅（审校）2
1.温州医科大学第一临床医学院,浙江 温州 325000
2.台州学院医学院附属市立医院耳鼻咽喉-头颈外科,浙江 台州 318000

作者简介:孙栋勋,男,1987年生,硕士,主要从事鼻咽癌的诊断和治疗工作。

通讯作者:蔡志毅,联系电话:0576-88858023。

基金:浙江省医药卫生科技项目(2013KYB293);
摘要

表皮生长因子受体(EGFR)/磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(PKB,也称Akt)信号通路是生物体内一条非常重要的生存信号通路。EGFR通过二聚化后刺激Ras蛋白,导致磷酸化级联反应的发生来激活PI3K/Akt信号通路,从而引起肿瘤的发生发展。本文从EGFR/PI3K/Akt信号传导通路对肿瘤的调节机制等多个方面综述了EGFR/PI3K/Akt信号通路与肿瘤的关系。

关键词: 表皮生长因子受体; 磷脂酰肌醇3-激酶; 蛋白激酶B; 肿瘤
中图分类号:R446.1 文献标志码:A 文章编号:1673-8640(2014)07-0768-06
EGFR/PI3K/Akt signaling pathway with tumor
SUN Dongxun1, CAI Zhiyi2
1.The First Clinical Medical Institute, Wenzhou Medical College, Zhejiang Wenzhou 325000, China
2.Department of Otolaryngology, Municipal Hospital Affiliated to Taizhou University School of Medicine, Zhejiang Taizhou 318000, China
Fund:
Abstract

Epidermal growth factor receptor(EGFR)/phosphatidylinositol-3-kinase(PI3K)/protein kinase B(PKB,or Akt) signaling pathway is a very important survival signaling pathway. EGFR dimerization pattern can stimulate Ras protein, which leads to a cascade of phosphorylation and activation of PI3K/Akt signaling pathway, and then leads to the occurence of tumors.This review summarizes the relationship between EGFR/PI3K/Akt signaling pathway and tumor by analyzing the function of EGFR/PI3K/Akt signaling pathway.

Keyword: Epidermal growth factor receptor; Phosphatidylinositol-3-kinase; Protein kinase B; Tumor
引言

表皮生长因子(epidermal growth factor,EGF)于1962年在新生鼠中被首次发现[ 1]。约20年后人表皮生长因子受体(epidermal growth factor receptor,EGFR)被分离纯化[ 2]。随着研究的深入,EGFR及其下游通路也不断被人们所了解。磷脂酰肌醇3-激酶(phosphatidylinosiyol-3-kinase,PI3K)/蛋白激酶B(protein kinase B,PKB,也称Akt)信号通路作为EGFR的一条下游通路在大多数人类肿瘤中表达失调。EGFR主要是通过二聚化后刺激Ras蛋白,导致磷酸化级联反应而激活PI3K/Akt信号通路,从而引起肿瘤的发生、发展,故有学者将其称为EGFR/PI3K/Akt信号传导通路。现已证实,在人类多种恶性肿瘤组织和肿瘤细胞株中,存在着EGFR的表达和功能异常[ 3, 4, 5, 6, 7, 8, 9, 10],包括膀胱癌、卵巢癌、鼻咽癌、乳腺癌、胶质细胞瘤、胰腺癌、前列腺癌、食管癌等等。研究已发现PTEN的失活必然导致PI3K/Akt通路的活化[ 11],而EGFR过表达或突变也会产生这种结果,而且活化的Akt具有多种生物学活性,可通过一系列蛋白的级联磷酸化促进肿瘤细胞的生长、增殖,抑制凋亡,促进侵袭和转移,调控肿瘤血管形成,耐受肿瘤的治疗等[ 12]。可见EGFR/PI3K/Akt信号传导通路的失调与肿瘤的发生、发展密切相关。我们从EGFR/PI3K/Akt信号传导通路的调节机制、细胞凋亡、细胞侵袭与转移、细胞周期调节、肿瘤的血管形成、肿瘤的治疗等多个方面综述了EGFR/PI3K/Akt信号通路与肿瘤的关系。

一、EGFR/PI3K/Akt信号传导通路对肿瘤细胞的调节
1.EGFR/PI3K/Akt信号传导通路的正调控

EGFR/PI3K/Akt信号传导通路的正调控包括2种形式:(1)配体激活EGFR后,接头蛋白Gab1被磷酸化,并作为核心蛋白大量召集下游蛋白,特别是PI3K;Gab1的C端特异性酪氨酸磷酸化后可与PI3K调节亚基的p85结合,从而使PI3K大量聚集在Gab1周围,而其N端的PH结构域则可以结合细胞膜上的PIP3,致使Gab1大量在细胞膜上聚集,从而加大信号的传递[ 13];(2)当在没有Gab1的情况下,EGFR只有与HER3形成二聚体才能使PI3K活化,该通路中活化的PI3K进一步催化胞质膜上PIP3的生成,后者与含有PH结构域的信号蛋白Akt结合而活化Akt,Akt又可以通过磷酸化作用激活其下游靶蛋白mTOR等的表达,mTOR磷酸化后又激活其直接作用底物P70S6K等,从而使细胞蛋白合成加快,细胞生长速度加快,进一步加速了肿瘤的恶化进程。

2.EGFR/PI3K/Akt信号传导通路的负调控

负调控主要依赖于抑癌基因 PTEN的调节。 PTEN是近来发现的一种新的肿瘤抑制基因,并被视为p53之后最重要的抑癌基因,其基因产物对具有脂质磷酸酶活性和蛋白磷酸酶活性的底物有很强的催化作用。PTEN可以使其下游通路中的底物PIP3去磷酸化转变成PIP2而降解,阻断Akt及其下游相关靶蛋白的活化[ 14]。此外,还有研究表明磷酸酶能够调节p85亚基的磷酸化而抑制PI3K的活化,从而阻断信号的传递[ 15]。

二、EGFR/PI3K/Akt信号传导通路与肿瘤细胞凋亡

EGFR/PI3K/Akt信号通路可以阻止肿瘤细胞启动程序性死亡,并促进肿瘤细胞增殖、抑制凋亡,从而促进肿瘤细胞的生存。该通路抗凋亡作用可能的作用主要包括以下途径。

1.Bad途径

Bad为Bcl-2家族成员。通路中Akt磷酸化的激活可以作为Bad强有力的激酶,使Bad的Ser136位点磷酸化,从而阻断Bad诱导细胞凋亡[ 16, 17]。

2.调节核转录因子κB (nuclear factor-κB, NF-κB)活性

有研究表明抑制NF-κB并激活c-Fos/活化蛋白转录因子-1 (transcription factor activator protein-1, AP-1)可以显著增强那些具有凋亡抵抗作用的前列腺癌细胞对肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)促凋亡作用的敏感性,而任何单独一种途径都只能获得部分效应[ 18]。

3.跨膜蛋白受体Notch途径

Notch在多种肿瘤中都起着致癌基因或抑制肿瘤的作用。在星形胶质细胞瘤细胞中,Notch通过EGFR/PI3K/Akt信号通路发挥抑癌作用,而Notch1和Notch2则扮演着不同的角色。敲除Notch1基因表达的相关siRNA可以有效的抑制肿瘤的增殖,诱导肿瘤细胞凋亡;而上调Notch2的表达则可以达到同样的效果[ 19]。

4.组织因子(tissue factor,TF)途径

通过对乳腺癌mpa-mb-231细胞的研究发现,PI3K抑制剂LY294002和Akt抑制剂A6738可抑制 TF启动子的活性,从而降低 TF mRNA及相应蛋白的表达,而EGFR抑制剂厄洛替尼(Erlotinib)和特异性降解 TF mRNA的siRNA也可显著抑制 TF启动子活性,降低其表达,从而促进肿瘤细胞的凋亡。上述调节方式在对卵巢癌OVCAR-3和SKOV-3细胞的研究中也同样被观察到[ 20]。

5.转化生长因子(transforming growth factor, TGF)途径

TGF可通过上调SOX-2的表达促进肿瘤细胞的凋亡[ 21]。同样的结果在对人卵巢颗粒细胞癌细胞的研究中也可观察到[ 22]。TGF-β可通过EGFR/PI3K/Akt信号通路在转录水平上抑制TGIF(TG相互作用因子)的表达,从而促转录细胞凋亡[ 23]。

6.茶多酚途径

通过对大鼠喂食含茶多酚(儿茶素、茶黄素)的乌龙茶、普洱茶以及绿茶等茶叶,可以抑制脂肪酸合成酶基因的表达,从而促进细胞凋亡[ 24]。

三、EGFR/PI3K/Akt信号传导通路与肿瘤细胞侵袭和转移

EGFR/PI3K/Akt信号通路在肿瘤的侵袭转移中通过各种途径扮演着及其重要的角色。通过上皮-间质细胞转换(epithelial mesenchymal transition,EMT)方式来调节细胞间的黏附力,从而使上皮细胞具有类似纤维母细胞样特性,进而增强人唾液腺腺样细胞癌细胞系ACC细胞在体内的运动能力,加快肿瘤转移[ 25]。研究表明,通过对Akt1的调节抑制,可使小鼠胚胎成纤维细胞迁移力受损下降,而上调Akt1的表达可以恢复细胞的迁移能力[ 26]。在视网膜色素上皮细胞(retinal pigment epithelium, RPE)中,EGF可以介导其受体EGFR,并通过PI3K/Akt通路的磷酸化促进RPE细胞系ARPE-19细胞的迁移侵袭,而应用EGFR和PI3K抑制剂后,ARPE-19的侵袭转移能力则被抑制[ 27]。人为地将选择性EGFR酪氨酸激酶抑制剂吉非替尼(Gefitinib)加入乳腺癌细胞株MDA-MB-231细胞中,可发现吉非替尼能抑制EGFR及其下游关键蛋白的磷酸化,并呈现剂量依赖性。而在划痕实验中,吉非替尼则相比对照组能够显著延长伤口愈合时间,抑制细胞扇状伪足的形成,另可改变细胞骨架微丝结构,减少细胞的迁移数量[ 28]。通过研究基因型为P53-R175H的P53突变和子宫内膜癌细胞(PLE)的关系发现,P53-R175H突变细胞中EGFR/PI3K/Akt信号通路过度表达,细胞侵袭力强,而抑制P53-R175H的短发卡RNA则可以衰减EGFR/PI3K/Akt通路的表达,从而显著抑制细胞的侵袭迁移[ 29]。

四、EGFR/PI3K/Akt信号传导通路与肿瘤细胞周期调节

EGFR/PI3K/Akt信号通路可以通过激活细胞周期依赖性蛋白激酶(cyclin dependent kinase,CDK)4来抑制P21Cipl和P27Kip2(P21和P27为细胞周期蛋白依赖性激酶抑制蛋白)的表达,使其在胞浆中堆积而无法与CDK连接,进而促进细胞由G1期向S期进展,促进细胞的增殖分化和肿瘤的发生、发展[ 30]。研究发现,在前列腺癌细胞中,金属蛋白酶17(adisintegrin and metalloprotease 17,ADAM17)可以激活EGFR/PI3K/Akt信号通路,并促进P21、P27和细胞周期素E的上调以及CDK2的下调,致使细胞从G1期向S期转化,加快细胞增殖分化;相反,下调ADAM17可以得到相反的结果[ 31]。而将P27转染到肾上腺嗜铬细胞瘤PC3细胞株中,转染后的细胞内EGFR/PI3K/Akt信号通路受抑制,致使细胞停滞在G0/G1阶段,并促使细胞凋亡[ 32]。TGF-α是一种转化生长因子,它通过抑制 Sox-2基因的表达,从而抑制细胞从G1期向S期进展[ 33],并减少细胞周期蛋白D1的表达,使细胞停滞在G0/G1阶段。而Akt的磷酸化则可有效减少细胞周期蛋白D1的降解,从而促进细胞增殖[ 34]。通过对过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor-γ, PPAR-γ)激动剂罗格列酮(Rosiglitazone)的研究发现,罗格列酮可以抑制细胞周期蛋白D1和A的表达,并强效抑制活性氧的生成而减少EGFR的活化,有效影响肾小球系膜细胞的增殖分化[ 35]。

五、EGFR/PI3K/Akt信号传导通路与肿瘤血管形成

在肿瘤发生发展的生理和病理过程中,PI3K/Akt信号通路均发挥着极其重要的作用[ 36]。Hsieh等[ 37]研究发现,在脑组织微血管内皮细胞中,内皮素-1通过酪氨酸激酶C-SRC介导EGFR/PI3K/Akt信号通路发生级联反应,激活C-Jun/AP-1蛋白偶联并结合到COX-2启动子相应位点上,促使环氧合酶COX-2转录表达,并促进前列腺素E2(prostaglandin E2,PGE2)的生物合成和释放,进而促进血管形成。以上这一过程在非小细胞肺癌中也可以被观察到[ 38]。PI3K/Akt通路还可上调氧诱导因子1α(hypoxia-inducible factor 1α,HIF-1α),HIF-1α可促进强效促血管生成剂血管内皮生长因子(vascular endothelial gronth factor, VEGF)的合成和分泌,促使血管形成[ 39]。通过研究大鼠平滑肌细胞与动脉粥样硬化的关系以及非小细胞肺癌特点时发现,ATP可以增加COX-2(环氧化酶-2)的表达来促PGE2合成分泌,并促使VEGF的合成分泌,使血管内皮细胞活力加强而加速血管形成[ 40]。肿瘤的生长转移有赖于血管,而PTEN能有效抑制PI3K/Akt通路致使血管形成受抑制[ 41]。

六、EGFR/PI3K/Akt信号传导通路与肿瘤的治疗
1.EGFR/PI3K/Akt信号通路与放疗

EGFR/PI3K/Akt信号通路不仅影响肿瘤细胞的增殖分化、侵袭转移,而且在肿瘤的治疗中也起到关键作用。在对乳腺癌的放疗过程中发现,EGFR/PI3K/Akt信号通路与放疗的敏感性和抗辐射性有关,且与放射过程中肿瘤细胞的增殖、缺氧密切相关[ 42]。在对卵巢癌治疗中观察到,曲古抑菌素A可瞬时激活EGFR/PI3K/Akt信号通路,诱导凋亡抑制蛋白Survivin的表达,促进细胞存活,而应用EGFR抑制剂PD153035或PI3K抑制剂LY294002则可以通过有效抑制曲古抑菌素A的作用,促使细胞死亡[ 43]。另外,Koon等[ 44]在治疗鼻咽癌时,联合应用EGFR抑制剂AG1478和Zn-BC-AM PDT放射治疗可明显阻断EGFR/PI3K/Akt信号通路。这一放疗技术可以对晚期鼻咽癌进行治疗。

2.EGFR/PI3K/Akt信号通路与化疗

在研究应用顺铂对肝细胞癌进行化疗时发现,过表达ADAM17可以介导EGFR这一通路抑制顺铂导致的细胞缺氧,使HIF-1α表达上调,并使caspase-3和DNA修复酶——多聚ADP核糖聚合酶(poly ADP-ribose polymerase, PARP)在细胞内积累,从而产生顺铂耐药,使细胞存活。然而应用EGFR抑制剂AG1478和PI3K抑制剂LY294002却可以阻断ADAM17所诱导的顺铂耐药性[ 45]。在高表达EGFR和PTEN突变的乳腺癌MDA-MB-468细胞中,联合应用EGFR抑制剂和PI3K抑制剂可以有效逆转癌细胞的恶性表型,并加速癌细胞的衰变凋亡[ 46]。而且EGFR抑制剂和mTOR抑制的联合应用也正进一步被研究用于临床治疗[ 47]。感染人类乳头瘤病毒(human papilloma virus, HPV)的肺癌中,细胞凋亡抑制蛋白2(c inhibitors of antiapoptosis protein 2,cIAP2)的开放阅读框架E6表达增多,并结合NF-κB和环磷酸腺苷反应元件结合蛋白(cAMP-responsive element binding protein,CREB)使EGFR/PI3K/Akt信号通路磷酸化激活,促进细胞对顺铂的耐药性。而在应用EGFR抑制剂或PI3K抑制剂与顺铂联合治疗后,疗效却大大提高,顺铂耐药性明显降低,并可加速癌细胞凋亡[ 48]。当应用厄洛替尼治疗非小细胞肺癌发生耐药时,应用组蛋白去乙酰化酶抑制剂MPT0E028可以明显降低厄洛替尼耐药性的发生。MPT0E028可以提高组蛋白H3乙酰化水平,并诱导凋亡蛋白PARP和caspase-3等的表达,从而显著抑制肿瘤的生长。而这些抑瘤效果却不受基因编码的EGFR或 K-ras突变状态的影响[ 49]。绝大多数大肠癌患者存在 K-ras基因突变。近来有学者应用EGFR抗体治疗 K-ras G13D突变的大肠癌患者,取得了良好的疗效,并针对47例大肠癌患者,应用肽核酸钳制聚合酶链反应(peptide nucleic asid-polymerase chain reaction, PNA-PCR)技术计算出 K-ras突变程度与EGFR抗体治疗的疗效关系:疾病控制率在低 K-ras突变(<30%)组约为44.4%,中等突变(30%~80%)组为5.6%,而高突变(>80%)组则为12.5%,通过分析得出 K-ras低突变程度很可能受益于EGFR抗体的治疗[ 50]。

七、展望

综上所述,EGFR/PI3K/Akt信号传导通路与肿瘤存在着广泛而密切的联系,其失调不仅促进肿瘤的恶性增殖、侵袭迁移、血管形成等,而且在肿瘤的放化疗中也起到非常重要的作用,所以这条通路也成为目前研究的热点。目前基于EGFR、PI3K、Akt等抑制剂与放化疗联合应用的治疗技术才刚刚起步,还不是很成熟,其作用机制也不完全清晰,有待进一步研究探索。因此,通过深入研究并揭示EGFR/PI3K/Akt信号通路的分子机制将有助于清楚地了解肿瘤发生、发展的本质,并为临床治疗工作提供新的治疗靶点和治疗策略,同时如何选择特异性的抑制剂进行个体化治疗,以及避免相应的不良反应也将成为今后研究的重点。

The authors have declared that no competing interests exist.

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