修回日期: 2013-05-18
接受日期: 2013-06-05
在线出版日期: 2013-07-18
化疗在胃癌的治疗中占有重要地位, 铂类药物是常用的胃癌化疗药物之一, 不同个体对铂类药物的敏感性差异很大. 乳腺癌易感基因1(breast cancer susceptibility gene 1, BRCA1)是一种抑癌基因, 与铂类药物的敏感性有关. 目前针对BRCA1的研究多集于乳腺癌方面, 而在胃癌中的研究很少. 本文就BRCA1的结构与功能, BRCA1与胃癌关系的相关研究进展进行综述.
核心提示: 乳腺癌易感基因1(breast cancer susceptibility gene 1, BRCA1)参与胃癌的发生, 并与胃癌的分化、分期、预后有密切关系. BRCA1的表达水平可作为以铂类为基础的药物化疗的胃癌患者生存时间的预测分子.
引文著录: 钟国栋, 余英豪. BRCA1在胃癌中的研究进展. 世界华人消化杂志 2013; 21(20): 1939-1944
Revised: May 18, 2013
Accepted: June 5, 2013
Published online: July 18, 2013
Chemotherapy occupies an important position in the treatment of gastric cancer. Platinum drugs are commonly chemotherapy drugs for gastric cancer; however, sensitivity to these drugs varies among different patients. The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene that is associated with sensitivity to platinum drugs. At present, the research on the BRCA1 gene is mainly focused on breast cancer, and there have been fewer studies on gastric cancer. This paper will give an overview of the structure and function of the BRCA1 gene and the relationship between BRCA1 and gastric cancer.
- Citation: Zhong GD, Yu YH. Progress in research of the BRCA1 gene in gastric cancer. Shijie Huaren Xiaohua Zazhi 2013; 21(20): 1939-1944
- URL: https://www.wjgnet.com/1009-3079/full/v21/i20/1939.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i20.1939
胃癌是最常见的消化系恶性肿瘤之一, 在我国胃癌的发病率居恶性肿瘤的第2位, 死亡率居恶性肿瘤死因的第3位[1]. 迄今我国胃癌患者术后5年生存率较低, 多数患者术后还需接受化疗、放疗等综合治疗, 化疗在胃癌的治疗中占有重要地位[2]. 铂类药物是常用的胃癌化疗药物之一, 不同个体对铂类药物的敏感性差异很大. 研究表明乳腺癌易感基因1(breast cancer susceptibility gene 1, BRCA1)与铂类药物的敏感性有关, 目前针对BRCA1的研究多集中于乳腺癌方面, 而在胃癌中的研究很少. 本文就近年来BRCA1在胃癌的研究进展进行综述.
BRCA1基因是1990年Hall等[3]通过对23个乳腺癌家族进行基因连锁分析发现的与家族性乳腺癌有关的易感基因. 而后Narod等[4]调查了5个遗传性乳腺癌/卵巢癌大家族, 进一步验证了Hall等[3]的发现. 1994年Miki等[5]通过采用定位克隆的方法分离出BRCA1基因, 后被命名为BRCA1.
BRCA1定位于染色体17q21 D17S1321-D17S1325之间, 长约81 kb, 共有24个外显子, 第1,4号外显子不编码氨基酸, 第11号外显子最长, 约3.4 kb, 占整个编码区的60%. BRCA1基因编码一个含1863个氨基酸的核蛋白, 称为BRCA1蛋白, 其分子量为220 kb. BRCA1蛋白具有以下特征性结构域[6]: (1)N-端的锌指结构, 该结构富含半胱氨酸和组氨酸, 是蛋白质-蛋白质或蛋白质-DNA相互作用的主要功能域[7]; (2)核定位区, 负责编码两个核定位信号(NSL1和NSL2), 是BRCA1核转运所必需的. 外显子11的编码产物中含有非常重要的NLS蛋白, 其突变所致的截短蛋白缺乏NLS, 可致BRCA1蛋白的转运失败, 引起核内BRCA1蛋白缺失, 而在细胞浆中错位表达; (3)Rad51结合区, 与DNA损伤修复蛋白Rad51结合, 参与DNA损伤修复过程; (4)粒素区, 位于1214-1223氨基酸残基之间; (5)BRCT区, C-端含有2个长85-95个氨基酸残基的BRCT基序, 中心部分为保守的疏水氨基酸. 该功能区普遍存在于DNA修复和细胞周期调控相关蛋白中, 对细胞周期监控、转录激活、DNA损伤修复起重要作用. BRCA1中多数与肿瘤相关的突变均可导致BRCT功能缺失[8]; (6)转录活性区, BRCA1蛋白C-端富含酸性氨基酸, 提示该区具有转录激活作用.
BRCA1蛋白具有抑制肿瘤生长的作用. BRCA1蛋白不仅参与细胞周期调控、DNA损伤修复、基因转录及细胞凋亡等多种重要细胞活动, 而且在维持基因组稳定性中起重要作用[9-12]. BRCA1基因若发生突变, 将导致其编码的基因产物结构或功能的异常, 并失去原有的功能, 最终将可能导致肿瘤的发生.
1.2.1 参与细胞周期调控: 正常情况下, BRCA1蛋白可与细胞周期素依赖性激酶及细胞周期素A、周期素D结合, 随细胞周期时相变化, 呈现磷酸化和去磷酸化两种状态的互换, 即在G1晚期和S期呈现高度磷酸化状态, 在M期后转为去磷酸化状态[13,14]. 已有研究表明BRCA1在细胞周期调控中起着重要作用[15]. 在G1/S期, BRCA1以锌指结构域作为蛋白质-蛋白质相互作用的主要作用域, 通过转录因子E2F的作用和细胞周期蛋白CDKS复合物的磷酸化, 抑制细胞进入增殖期, 阻止细胞分裂, 诱发细胞凋亡. BRCA1能与p53蛋白直接结合, 并通过p53激活P21的转录, p21作为细胞周期抑制因子抑制CyclinE-CDK2的活性, 从而引起G1期阻滞[16]. 虽然有研究表明BRCA1上调p21的表达并不依赖于p53的存在[17],但是也有研究表明BRCA1诱导的G1/S细胞周期停滞需要p53的参与.
1.2.2 参与DNA损伤修复: DNA损伤时, BRCA1能阻断细胞周期使其停留在特定的检测点, 在BRCA1的招募下, 多个修复蛋白形成复合体, 目前发现较重要的通路与蛋白复合体有3个[18-21]: (1)ATR-TopBP1通路. 双链DNA因紫外线损伤,引起ATR发生磷酸化, 激活下游基因Chk2. Chk2能磷酸化BRCA1, 磷酸化的BRCA1作为一个信号因子将感知的DNA损伤信号传递给DNA修复体系, 从而调节DNA双链的断裂与修复[22]. 同时Chk2使G2/M期细胞阻滞, 使DNA在尚未进入分裂之前得到修复[23]; (2)BRCA1-RAD-50-MRE11-NSB1聚体. DNA损伤时, BRCA1可与R-M-N复合物相互作用[24], 通过同源重组(homologous recombinational repair, HRR)和非同源末端连接(non-homologous end-joining, NHEJ)两条途径协调DNA损伤修复; (3)BRCA1-BRCA2-RAD51三聚体. DNA受损时, BRCA1复合物可能通过HRR途径参与DNA修复功能[25,26]. De Nicolo等[27]研究显示BRIP1/BACH1编码的蛋白质产物能与BRCT重复序列直接结合发生作用, 参与BRCA1基因的DNA损伤和修复过程.
1.2.3 参与转录调控: BRCA1蛋白具有转录活化和转录抑制双重作用, N-端的锌指结构具有DNA结合功能, C-端的"酸性基团"具有反向激活功能[28]. Mullan等[29]认为BRCA1 C-末端酸性基团可与GAL4 DNA结合, 激活GAL4依赖的启动子转录, 但是BRCA1只能非特异性结合DNA序列, 其转录活性依赖特异性结合DNA的转录因子作为导向. BRCA1与某些转录因子或转录调节因子互相作用可增强或抑制这些因子的转录. 如BRCA1可作为p53辅激分子, 通过外显子11(氨基酸224-500)和BRCT结构域上(氨基酸1760-l863)两个结合位点直接结合p53, 选择性增强与DNA修复和细胞周期阻滞有关的基因[30], 而p53也能反过来抑制BRCA1的表达, 借此达到稳定自身的作用[31]. BRCA1还可与C-myc结合, 抑制C-myc对端粒酶反转录酶(hTERT)的转录调节[32]. 此外, BRCA1还可与CtIP、CtBP等因子相互作用, 调节下游基因的转录活性, 发挥不同的功能.
1.2.4 中心体的复制: BRCA1与负责微管及有丝分裂纺锤体形成的γ-微球蛋白相互作用, 在中心体复制中起负性调节作用[33]. BRCA1基因突变可导致中心体扩增, 染色体不对称分离, 非整倍体增加, 最终可能导致肿瘤形成. 因此, BRCA1是维持染色体稳定的必需基因, 在有丝分裂中具有重要作用.
2 BRCA1在胃癌中研究
胃癌的发生是多基因多步骤的病理过程, 该过程涉及多种原癌基因的激活和抑癌基因的失活. 目前研究表明, 抑癌基因的失活在肿瘤的发展中所起的作用可能比原癌基因的活化更常见、更重要. BRCA1是抑癌基因, BRCA1基因编码的BRCA1蛋白有抑制肿瘤生长的作用, 在维持基因组稳定性中起重要作用. 当BRCA1发生基因突变使其蛋白表达结构异常或表达水平下降, 或由于其他原因使BRCA1正常功能减弱或消失, 可能导致细胞恶变和胃癌的发生[34,35].
陈永宏等[36]通过检测61例胃癌组织与正常组织中BRCA1的表达, 发现胃癌组织中BRCA1蛋白表达率比正常组织表达率显著降低. Kim等[37]通过对318例接受手术治疗与D2根治术胃癌患者BRCA1基因表达检测, 发现其中155例胃癌患者(48.7%)BRCA1是阴性表达、96例胃癌患者(30.2%)低表达、67例胃癌患者(21.0%)高表达. 但也有研究表明胃癌的发生与BRCA1的过表达有关, 且随着原发肿瘤向深处的浸润, BRCA1蛋白阳性表达率无显著性差异. 提示胃黏膜一旦发生癌变,即可获得稳定的BRCA1蛋白表达[38]. 此外, Moiseyenko等[39]研究认为胃癌可能是BRCA1相关的遗传性肿瘤综合征.
启动子异常甲基化是抑癌基因失活的一个重要机制, 主要发生在启动子CpG岛内. 在正常情况下这些位点处于完全未甲基化状态, CpG岛发生异常甲基化往往会改变基因的表达模式, 导致抑癌基因的转录失活或沉默. 失活的抑癌基因不能负调控细胞周期增殖, 使细胞周期进展得以进行, 从而导致细胞恶性改变, 形成肿瘤[40,41]. 目前研究表明, BRCA1基因5'端启动子CpG岛异常甲基化, 使得该区域的组蛋白去乙酰化且核小体在空间排列上更加均匀致密, 这种状态会直接抑制转录, 增强转录抑制蛋白的作用, 使基因转录失活而失表达. Zavala等[42]通过采用分层聚类的方法对83例浸润性胃癌抑制基因甲基化进行研究, 结果表明在胃癌中BRCA1发生高频甲基化, 但是抑癌基因指数与胃癌临床病理特征无明显相关. 启动子异常甲基化是肿瘤发生的早期事件[43], 具有细胞和组织特异性. Bernal等[44]研究发现BRCA1甲基化可能与早发性胃癌有关.
基因的遗传不稳定性改变, 可导致抑癌基因功能障碍或缺失, 是引起肿瘤发生的重要因素之一. 基因的微卫星不稳定性(microsatellite instability, MSI)和杂合性缺失(loss of heterozygosity, LOH)是胃肠道肿瘤常见的遗传改变. Chen等[45]通过检测37例胃癌组织和相应的非胃癌组织中BRCA1基因的MSI和LOH, 显示BRCA1的MSI与LOH与胃癌的TNM分期有密切相关, BRCA1基因MSI在TNMⅠ-Ⅱ期胃癌病例中的阳性率远高于TNM Ⅲ-Ⅳ期病例, 而BRCA1基因LOH在胃癌TNMⅠ-Ⅱ期病例中的阳性率低于TNM Ⅲ-Ⅳ期病例, 但两者与淋巴结转移, 组织学类型或肿瘤分化无明显关系. 因此, BRCA1基因MSI可作为散发性胃癌早期的一个分子标志, LOH可以作为散发性胃癌晚期的一个预后因子. BRCA1蛋白表达与TNM分期、胃癌的分化有关. BRCA1蛋白在TNMⅠ+Ⅱ期中的阳性率远高于TNM Ⅲ+Ⅳ期病例. BRCA1蛋白的表达与胃癌分化程度呈正相关, 随着管状腺癌分化程度的升高, 其阳性率呈明显增高趋势, 这提示BRCA1蛋白可改善患者预后, 并可能具有抑制胃癌向低分化发展的作用. Zhang等[46]研究发现BRCA1表达缺失与胃癌的扩散、分期有关, 而且BRCA1表达缺失的胃癌患者比BRCA1未缺失患者的生存期明显要短. 提示BRCA1表达缺失可能可作为胃癌进展的预测因子. Chen等[47]通过检测637例胃癌手术标本的BRCA1蛋白, 发现其中有219例胃癌标本BRCA1表达阳性, 且BRCA1表达与肿瘤分化有明显相关. 此外, 也有实验表明BRCA1、TRF1、TRF2、TIN2、TERT和KU70蛋白的表达与端粒缩短有关, 并可能导致胃癌的多阶段癌变[48], 这个发现可能是胃癌形成的新机制.
铂类药物(顺铂和草酸铂)是目前胃癌化疗常用的药物之一. 铂类药物进入肿瘤细胞后水解为双氯双氨铂, 由氯化物配合体所形成的水合物可以与细胞大分子的亲核性位点相作用, 并在细胞的DNA中形成Pt-DNA复合物, 导致DNA的链间或链内交链, 主要是1,2链间交联, 少数为1,3链间交联、长链交联以及DNA-蛋白交联, 引起DNA复制障碍、RNA转录抑制,阻碍细胞停滞于G2期. 这些停滞的细胞或进行DNA损伤修复或发生凋亡[49-52]. BRCA1作为一种负性调控因子参与细胞周期检测点的调节并可通过形成多种复合物参与DNA修复. BRCA1高表达使细胞修复能力增强, 使肿瘤细胞不易被顺铂杀死, 从而影响顺铂的耐药性[53,54].
低表达BRCA1的胃癌患者无病生存期(diseasefree survival, DFS)和总生存期(overall survival, OS)明显降低, 而BRCA1表达阴性的胃癌患者预后更差. 铂类辅助化疗能延长BRCA1阴性患者的DFS和OS, 但不能延长BRCA1阳性患者[37]. 然而也有研究认为BRCA1表达阳性患者接受铂的辅助化疗显示更好的预后. 张文君等[55]通过对74例采用5-氟尿嘧啶+草酸铂为主的化疗方案的胃癌患者进行研究, 结果显示BRCA1基因的表达水平与顺铂敏感性呈负相关, 低表达BRCA1的患者接受铂类化疗后生存时间较高表达的患者有延长趋势. Shim等[56]通过对200例应用顺铂和紫杉烷类药物治疗的患者进行研究, 发现BRCA1 TT纯合子突变能显著延长患者总体生存率和存活期, 并提出BRCA1 TT基因型可能适度成为进展期胃癌的预后标志物. 因此, 在某种程度上BRCA1的表达水平可作为以铂类为基础的药物化疗的胃癌患者生存时间的预测分子.
BRCA1与胃癌的发生、分化、分期、预后及治疗均具有密切关系, 通过检测BRCA1的表达情况可用于指导胃癌的个体化治疗以及生存期的预测. 因此明确BRCA1在胃癌中的作用机制, 以适应肿瘤治疗的需要, 为肿瘤的防治提供新方法, 将成为今后值得进一步深入研究的问题.
胃癌是最常见的消化系恶性肿瘤之一, 铂类药物是常用的胃癌化疗药物, 乳腺癌易感基因1(breast cancer susceptibility gene 1, BRCA1)与铂类药物的敏感性有关. 目前针对BRCA1的研究多集中于乳腺癌方面, 而在胃癌中的研究很少.
肖秀英, 副主任医师, 上海市徐汇区中心医院肿瘤科; 于颖彦, 教授, 瑞金医院消化外科研究所与器官移植中心
BRCA1是乳腺癌的易感基因与胃癌的发生、分化、分期、预后及治疗均具有密切关系, 但是具体机制还不是很清楚.
本文发现BRCA1表达缺失与胃癌的扩散、分期有关, 而且BRCA1表达缺失的胃癌患者比BRCA1未缺失患者的生存期明显要短.
本文内容新颖, 涉及BRCA1表达缺失与胃癌的扩散、分期有关的内容, 对基础研究和临尿应用均有较重要的指导价值.
本文总结了目前BRCA1参与胃癌发生可能的机制, 并指出尚存争议及未阐明的问题, 为进一步深入研究胃癌发病机制提供了方向.
本文立题新颖, 相关报道不多, 文章的科学性、创新性和可读性可以较好地反映我国结直肠癌临床和基础研究的先进水平.
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