PDCD4基因在肿瘤中表达的调控及其功能的研究进展

薛迪新 陈积贤

●综 述

PDCD4基因在肿瘤中表达的调控及其功能的研究进展

薛迪新 陈积贤

PDCD4基因是一种新的抑癌基因，也是一种与细胞凋亡相关的基因。近年来研究表明在许多实体瘤中PDCD4基因的表达下降，甚至出现缺失。低表达的PDCD4基因促使肿瘤细胞增殖、侵袭和转移。一般情况下，低表达的PDCD4提示肿瘤患者的不良预后，故PDCD4基因可能成为生物治疗新的靶点。从分子水平阐述PDCD4基因的表达调控机制和功能，对恢复PDCD4基因的表达来治疗肿瘤的意义重大，同时也可以从PDCD4基因的角度去阐述肿瘤的发生、侵袭和转移的机制。本文主要是将近些年来PDCD4基因的功能与调控作一总结，并阐述PDCD4表达与肿瘤患者预后的关系。

1 PDCD4基因的发现及其编码的蛋白结构

1995 年，为了阐明细胞凋亡的分子机制，Shibahara K等[1]采用差异显示法在各种凋亡细胞系中分离出cDNA克隆，在这些cDNA克隆中，MA-3 mRNA的表达被诱导。之后陆续克隆出鸡PDCD4基因[2]和鼠的DUG基因[3]等，统称为PDCD4。人类PDCD4基因定位于染色体10q24[4]，其表达的蛋白经序列分析表明由469个氨基酸组成，包括N末端结构域、C末端结构域和2个保守的α螺旋MA-3结构域[5]。N末端和C末端结构域可能是PDCD4蛋白核定位信号区，但是关于PDCD4蛋白亚细胞定位的报道存在争议。有文献报道PDCD4蛋白定位在正常细胞的胞核和肿瘤细胞的胞质中[6-7]，但也有文献报道存在相反的分布[8]，这可能是由于PDCD4在细胞核与质之间的转运引起的[9]。MA-3结构域通过与翻译起始因子相互作用影响PDCD4的翻译，包括eIF4GI、eIF4GII和eIF4A[10-11]。

2 PDCD4的功能

2.1 调节基因转录的功能 PDCD4蛋白能调节基因的转录从而发挥特定的生物学功能。用siRNA-Pdcd4转染GEO细胞株，导致细胞u-PAR mRNA和蛋白的表达水平升高，促进肿瘤细胞的侵袭。进一步用染色质免疫共沉淀技术（chromatin immunoprecipitation，ChIP）分析表明转录因子SP1/SP3与u-PAR基因的启动子元件-152/-135和-380/-354相互作用，调节u-PAR基因的转录[12]。而在乳腺癌细胞株中，PDCD4表达能增加TIMP2基因的转录，抑制乳腺癌细胞的转移[13]。在GEO细胞株中，敲除PDCD4能上调Snail蛋白来抑制E-cadherin的表达，刺激β-catenin/Tcf转录复合物依赖的转录，从而促进u-PAR和c-myc基因的转录，进一步用ChIP分析表明β-catenin/Tcf与u-PAR和c-myc基因的启动子结合来激活基因的转录，u-PAR和c-myc基因与肿瘤细胞转移相关，当敲除u-PAR和c-myc时，能够抑制GEO-shPdcd4细胞的转移[14]。此外，PDCD4蛋白通过直接抑制c-Jun的磷酸化，抑制转录因子AP-1的表达，从而抑制了细胞的恶性转化[15-16]。转录因子AP-1可以诱导血管生成素Ang-2的转录[17]，用siRNA-Pdcd4转染细胞株Bon-1和HCT116，PDCD4表达下降，而Ang-2 mRNA及其蛋白质表达升高，进一步用血管生成分析法表明高表达Ang-2能刺激血管的形成[18]。PDCD4还能与转录因子Twist1相互作用，导致Twist1的靶基因YB-1表达下降，从而抑制肿瘤细胞的增殖[19]。

2.2 调节基因翻译的功能 PDCD4蛋白不仅可以抑制帽子依赖的翻译，还可以抑制内核糖体进入位点（internal ribosome entry site，IRES）依赖的翻译。真核生物翻译起始因子eIF4A是依赖于ATP的RNA解旋酶，能展开5′mRNA的二级结构，酵母双杂交技术分析表明PDCD4蛋白能与翻译起始因子eIF4A结合，抑制帽子依赖的翻译，进而抑制AP-1的反式激活，从而抑制细胞的恶性转化[11]。PDCD4表达抑制JNK的活性，抑制c-jun磷酸化，进而抑制真核生物翻译起始因子eIF4E的表达和磷酸化，从而抑制帽子依赖的翻译，而用H2O2处理肝癌细胞株MHCC97L后，eIF4E的表达和磷酸化水平升高，促进金属蛋白酶MMP-2和MMP-9表达水平升高，从而促进肝癌细胞的转移[20]。PDCD4能对DNA的损伤产生应答反应。PDCD4蛋白与eIF4A结合后，抑制eIF4A与p53 mRNA 5′非编码区结合，从而抑制p53 mRNA的翻译，用DNA损伤剂处理细胞后，PDCD4的表达下降，促进p53 mRNA的翻译[21]，有利于DNA损伤的修复。XIAP和Bcl-xL mRNA的5′非编码区包含IRES元件，PDCD4蛋白直接与XIAP和Bcl-xL mRNA的IRES元件结合，抑制48S起始复合物的形成，从而抑制XIAP和Bcl-xL mRNA的翻译[22]。除此之外，PDCD4蛋白还可以直接调节基因的翻译。c-myb编码区包含PDCD4的反应元件，此反应元件存在于c-myb编码区的XmaI到SalI之间，PDCD4蛋白的N端结构域与c-myb mRNA中的PDCD4的反应区域直接结合抑制c-myb mRNA的翻译[23]。

此外，PDCD4的表达还可以使肿瘤细胞对某些化学物质或射线的敏感性发生变化。在正常生长的条件下，功能缺陷的PDCD4基因的鸡淋巴瘤细胞株DT40的增殖和细胞周期并没有受影响，但是在敲除PDCD4基因后，细胞对一些DNA损伤剂的敏感性增强，包括紫外线，依托泊甙和甲磺酸乙酯[24]。在胃癌细胞中敲除PDCD4基因后，癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）的敏感性减弱[25]。PDCD4基因的功能见图1。

图1 PDCD4基因的功能

3 PDCD4基因表达的调控

3.1 转录水平的调控 在转录水平调节PDCD4基因的表达，主要是通过一些转录因子与PDCD4基因的调控区相互作用，或甲基化5′CpG岛来实现的。转录因子v-Myb可以诱导鸡细胞中PDCD4基因的表达[26]，而敲除c-Myb基因，PDCD4基因的表达明显降低[27]。此外还有转录因子ZBP-89单独或与SP家族成员相互作用后通过与PDCD4基因的启动子结合促进PDCD4基因的转录[28]。在神经胶质瘤细胞株和组织中，PDCD4基因的5′CpG岛的甲基化，抑制PDCD4 mRNA的转录，同时用DNA甲基化转移酶抑制剂封闭5′CpG岛的甲基化后，细胞中PDCD4基因的表达可以恢复[29]。

3.2 转录后水平的调控 最近发现一种约由20个核苷酸组成的非编码的microRNA，它与靶基因转录的mRNA的3′非编码区结合，通过抑制mRNA翻译或直接降解mRNA来负性调节靶基因的功能[30-32]。许多实验均表明PDCD4是miR-21的靶基因，miR-21在转录后水平负性调节PDCD4的表达，包括大肠癌[33-35]，胃癌[36-37]，胰腺癌[38-39]，恶性胶质瘤[40]，膀胱癌[41]，子宫颈癌[42]等。此外，其他miRNA也同样调节PDCD4基因的表达。用miR-183转染人肝癌细胞株Huh7后，PDCD4蛋白的表达降低，用qRT-PCR技术检测25对临床活体肝癌及其正常肝脏组织中PDCD4 mRNA和miR-183的表达情况，结果显示miR-183的表达与PDCD4 mRNA的表达存在明显的负相关，进一步用生物信息学和荧光素酶报告基因检测证实miR-183是与PDCD4 mRNA 3′非编码区结合来负性调节PDCD4靶基因的表达[43]，表明PDCD4也是miR-183的靶基因。在大肠癌中，用上述同样的实验方法检测，结果显示microRNA-499-5p也可在转录后水平负性调节靶基因PDCD4的表达[44]。以上研究表明PDCD4基因的表达在转录后水平受到多种miRNA的调控。

3.3 其他信号转导通路对PDCD4基因表达的调控多种信号转导通路能共同调节基因PDCD4的表达。TGF-β信号转导通路可诱导肝癌Huh7细胞株PDCD4的表达，用信号通路抑制物Smad7转染细胞株后，可抑制TGF-β通路诱导PDCD4基因的表达[45]，但是在血管平滑肌细胞中，TGF-β通过上调miR-21的表达，负性调节PDCD4基因的表达[46]，此外用PKCδ和PKCεsiRNA转染肝癌细胞，可增强TGF-β诱导的PDCD4蛋白的表达[47]。当肿瘤细胞处在炎症的微环境下，能激活PI3K-mTOR信号途径，增强蛋白酶体降解PDCD4蛋白的作用，从而使肿瘤细胞中PDCD4蛋白的表达下降[48]。用PI3K的抑制剂处理胃癌和卵巢癌细胞株，抑制PI3KAkt信号转导通路，可使PDCD4蛋白的表达增加[25,49]。此外，激活FGF-2-S6K2信号途径，也可以使PDCD4蛋白磷酸化而被降解[22]。还有一些信号转导途径通过调节miR-21的表达，从而间接调节PDCD4基因的表达。在TLR4信号途径中，配体LPS（细菌内毒素）结合Toll样受体4（Toll-like receptor 4，TLR4）可激活衔接蛋白MyD88和NF-kappaB诱导miR-21的表达，可使PDCD4的表达降低[50]。在乳腺癌细胞株MCF-7中，透明质烷（HA）能与受体CD44的结合激活PKCε,后者磷酸化干细胞标志物Nanog，磷酸化的Nanog从细胞质进入细胞核，与RNase III DROSHA和RNA解旋酶p68结合，诱导miR-21的表达，从而负性调节PDCD4蛋白的表达[51]。在人类胶质母细胞瘤U251细胞株中，熊果酸可抑制TGF-β信号转导通路，进而抑制miR-21的表达，间接地促进了PDCD4蛋白的表达[52]。

此外，有一种称为抗亚砷酸盐蛋白-2（Ars2），它能够沉默miRNA表达[53]，在人类胆管癌细胞和组织中，Ars2的缺失可引起miR-21的表达增加，上调的miR-21可抑制PDCD4蛋白的表达[54]。PDCD4表达的调节机制见图2。

图2 PDCD4基因表达的调控机制

4 PDCD4基因在临床活体组织中的表达及预后判断

在许多实体肿瘤中，PDCD4的表达与肿瘤的临床预后密切相关。从正常、交界性到恶性卵巢癌组织中，PDCD4蛋白的表达逐渐下降，在卵巢癌患者中，PDCD4蛋白表达越低，患者生存率就越低，用免疫组化的方法检测发现正常卵巢细胞中的PDCD4蛋白主要定位在细胞核，而卵巢癌细胞的PDCD4主要定位在细胞质[55]，这可能与pAkt在细胞核和细胞质中的表达有关[56]。从正常大肠黏膜、腺瘤到大肠癌的演变过程中，PDCD4蛋白的表达逐渐下降，在此过程中，细胞PDCD4蛋白核与质表达的比率逐渐降低，pAkt与PDCD4蛋白从细胞核到细胞质的转移（即核与质的比率）之间存在负相关，表明PDCD4的转移受pAkt的调控。用Kaplan-Meier分析表明PDCD4蛋白表达越低，大肠癌患者的总生存时间越短，疾病相关存活率越低。PDCD4蛋白的缺失，提示大肠癌患者的不良预后[56]。在肾脏细胞癌中，PDCD4蛋白表达降低，与肾脏细胞癌的分级、分期和转移有关，即PDCD4蛋白表达越低，肾癌的分期越晚，越容易转移，患者的平均总生存时间越短，PDCD4蛋白的低表达提示肾脏细胞癌的不良预后[57]。Motoyama等[37]分析PDCD4 mRNA在105例胃癌中的表达与临床病理特征的关系，结果显示低表达的PDCD4 mRNA与胃癌的大小、浸润深度、淋巴结转移、血管转移和临床分期有关，表明低表达的PDCD4 mRNA提示胃癌的不良预后。Horiuchi等[58]分析326例大肠癌患者，在大肠癌Dukes′B和C期患者中，低表达的PDCD4 mRNA患者的总生存时间短，并且无瘤生存率低，在Dukes′D期的大肠癌患者中，低表达的PDCD4 mRNA患者的总生存时间短，但在Dukes′A期的患者中，低表达和高表达的PDCD4 mRNA患者之间的总生存时间和无瘤生存率均无差别。表明在Dukes′B、C和D期的患者中，低表达的PDCD4 mRNA提示大肠癌的不良预后。Gao等[29]研究表明在神经胶质瘤中，PDCD4基因5′CpG岛的甲基化导致PDCD4表达的沉默，在84例神经胶质瘤患者中，PDCD4表达的缺失提示患者的不良预后。

一般情况下，低表达PDCD4提示肿瘤患者的不良预后，但是有一部分高表达的PDCD4的肿瘤患者的预后也很差，经Powers等[59]的研究表明这与PDCD4蛋白N端被蛋白精氨酸甲基转移酶（PRMT5）甲基化，影响了PDCD4蛋白的功能有关。故PDCD4蛋白的功能对肿瘤患者预后的判断也是极其重要的。

5 结论

PDCD4表达的调节机制极其复杂，不仅在转录水平，转录后水平，而且一些信号转导通路也可以调节PDCD4的表达。PDCD4的表达也可以通过调节其他基因的转录和翻译，从而影响肿瘤细胞的增殖、侵袭和转移，形成复杂的调节网络。同时，PDCD4表达的缺失提示部分肿瘤患者的不良预后，因此，PDCD4可成为肿瘤治疗新的靶点，恢复PDCD4的表达有望成为肿瘤治疗新的策略。

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2012-07-19）

（本文编辑：胥昀）

瑞安市科技计划项目（201102039）

325200 瑞安，温州医学院附属第三医院肿瘤外科

陈积贤，E-mail:CJX1957@sohu.com.