ERCC1基因在食管癌中的研究进展

顺铂的细胞毒性主要在于与DNA特定碱基结合形成共价的顺铂-DNA加合物,导致DNA致命的损伤。顺铂-DNA加合物主要靠核苷酸切除修复（NER）系统来修复,ERCCI基因作为NER系统关键的修复基因,在铂类耐药过程中发挥重要作用。研究发现ERCC1的表达情况与恶性肿瘤的发病以及含铂方案的疗效相关。文章着重综述ERCC1基因在食管癌中的研究进展．包括与食管癌发生发展的关系、与含铂化疗方案有效率及预后的关系、基因多态性等。     

DNA修复基因 ERCC1在恶性肿瘤中的研究进展

核苷酸切除修复(NER)是机体维持基因组功能整体性、修复致癌因素所致的损伤及抗癌过程中的重要环节.NER途径是一个复杂的过程,其中 DNA损伤的识别/切除为其限速步骤.ERCC1是一种高度保守的 DNA核酸内切酶,是 NER途径的限速酶.ERCC1基因在癌症组织中是一种下调的基因,其表达低下可能与癌症的发生有关,而ERCC1基因的表达与癌症的化疗及放疗效果有关,特别是与使用以铂类为基础的化疗效果呈负相关,而且ERCC1基因可能是相关癌症的预后指标.显然,ERCC1是一个值得研究者关注的肿瘤相关基因.     

ERCC1基因在卵巢癌中作用的研究进展

卵巢癌是妇科恶性肿瘤中导致女性死亡的主要原因,目前主要治疗手段是手术切除并辅助以铂类为基础的化疗,但疗效受耐药性影响.顺铂耐药的机制尚不十分清楚,目前普遍认为核苷酸切除修复(nucleotide excision repair,NER)是顺铂耐药的重要机制之一.切除修复交叉互补基因1(excision repair cross-complementation gene group 1,ERCC1)是NER途径的限速酶,ERCC1表达与卵巢癌临床病理因素无明显相关性,ERCC1的表达与顺铂耐受性相关,下调ERCCI的表达可克服顺铂耐药性.     

食管鳞状细胞癌患者外周血和肿瘤组织中ERCC1及ERCC2表达的相关性研究

目的:探讨检测食管鳞状细胞癌患者外周血替代肿瘤组织中切除修复交叉互补基因1(excision repair cross-complementing 1,ERCC1)及ERCC2表达的可行性.方法:收集39例食管癌患者的术前外周血、肿瘤组织及癌旁正常组织,应用RT-PCR法检测ERCC1和ERCC2 mRNA的表达,应用ELISA法检测血清蛋白中ERCC1和ERCC2的含量,以10名健康志愿者外周血作为对照.结果: ERCC1和ERCC2 mRNA以及蛋白在健康志愿者外周血中的表达高于食管癌患者外周血(P<0.05);食管癌患者外周血中ERCC1和ERCC2 mRNA的表达水平与其在肿瘤组织中的表达水平呈明显的正相关关系(P<0.01).结论:食管鳞状细胞癌患者外周血中ERCC1和ERCC2 mRNA的表达水平能在一定程度上间接反映其在肿瘤组织中的表达水平.     

RNA干扰ERCC1基因表达对肺腺癌细胞A549/DDP顺铂耐药的影响

背景与目的核苷酸切除修复机制可修复顺铂(DDP)造成的DNA损伤,作为其中的关键酶之一,切除修复交叉互补基因1(excision repair cross-complementing gene 1,ERCC1)的表达可能与DDP耐药有关.本研究旨在探讨小干扰RNA沉默ERCC1基因表达对肺腺癌耐药细胞A549/DDP药物敏感性的影响.方法将体外设计合成针对ERCC1的小分子RNA(siRNA)转染A549/DDP细胞,RT-PCR检测ERCC1 mRNA水平;Western blot检测ERCC1蛋白表达的变化;MTT检测RNA干扰后细胞药物敏感性改变.结果 ERCC1 RNAi干扰后ERCC1 mRNA表达指数降低,明显低于对照组,干扰后ERCC1 mRNA表达抑制率为90.4%.转染ERCC1 siRNA降低TERCC1蛋白的表达水平.MTT显示分别用2μg/mL、4μg/mL、8μg/mL、16μg/mL、32μg/mL顺铂处理细胞48 h,转染ERCC1 siRNA细胞组较对照组敏感性明显增高,干扰前A549/DDP细胞IC50为12.49μg/mL,干扰后A549/DDP细胞IC50下降为9.27 μg/mL.结论 ERCC1siRNA干扰可以降低ERCC1的表达水平,并可提高A549/DDP细胞对顺铂的敏感性.     

DNA修复基因ERCC1在恶性肿瘤中的研究进展

核苷酸切除修复（NER）是机体维持基因组功能整体性、修复致癌因素所致的损伤及抗癌过程中的重要环节。NER途径是一个复杂的过程,其中DNA损伤的识别／切除为其限速步骤。ERCC1是一种高度保守的DNA核酸内切酶,是NER途径的限速酶。ERCC1基因在癌症组织中是一种下调的基因,其表达低下可能与癌症的发生有关。而ERCC1基因的表达与癌症的化疗及放疗效果有关,特别是与使用以铂类为基础的化疗效果呈负相关,而且ERCC1基因可能是相关癌症的预后指标。显然,ERCC1是一个值得研究者关注的肿瘤相关基因。     

ERCC1在晚期非小细胞肺癌中的表达及临床意义

目的:探讨核苷酸切除修复交叉互补基因1(ERCC1)在晚期非小细胞肺癌中的表达及其临床意义.方法:采用免疫组化S-P法检测78例Ⅲ期、Ⅳ期非小细胞肺癌患者中核苷酸切除修复交叉互补基因1(ERCC1)的表达情况.所有患者均以铂类为基础的化疗方案化疗.将患者化疗疗效和生存资料与ERCC1的表达进行比较.结果:78例患者ERCC1的阳性表达率为47.44%(37/78),ERCC1表达与患者性别、年龄、病理类型(鳞癌、腺癌)及临床分期无关;ERCC1阴性组化疗临床受益率是73.17%(30/41),ERCC1阳性组为51.35%(19/37),两组比较差异有统计学意义(χ2=3.9643,P=0.0465).ERCC1阳性组生存期为(21.1852±22.1134)月,ERCC1阴性组生存期为(12.375±10.0827)月,两组比较差异无统计学意义(P=0.0879).结论:ERCC1的表达与晚期非小细胞肺癌患者铂类药物化疗临床受益相关,检测ERCC1的表达对化疗药物的选择有一定指导意义.     

基因在卵巢癌中作用的研究进展

卵巢癌是妇科恶性肿瘤中导致女性死亡的主要原因,目前主要治疗手段是手术切除并辅助以铂类为基础的化疗,但疗效受耐药性影响。顺铂耐药的机制尚不十分清楚,目前普遍认为核苷酸切除修复(nucleotide excision repair,NER)是顺铂耐药的重要机制之一。切除修复交叉互补基因 1(excision repair cross-complementation gene group 1, ERCC1)是NER途径的限速酶,ERCC1表达与卵巢癌临床病理因素无明显相关性,ERCCl的表达与顺铂耐受性相关,下调ERCCI的表达可克服顺铂耐药性。     

切除修复交叉互补基因1（ERCC1）在卵巢癌中的研究进展

切除修复交叉互补基因1（ERCC1）是苷酸切除修复途径的关键基因。它参与了铂类药物耐药的形成．影响了正常组织的耐受性以及患者的预后。全文阐述ERCC1的生物学特性．分析ERCC1与铂类药物耐药性的关系及在卵巢癌中的研究进展。     

5 Aza CdR通过DNMT1调控卵巢癌细胞ERCC1基因甲基化及其表达

目的:研究5-氮杂-2'-脱氧胞苷(5-Aza-CdR)在卵巢癌细胞系SKOV3中对核苷酸切除交叉修复互补基因1(exeision repair cross complementation group 1,ERCC1)表达的影响及可能的机制.方法:设计特异性针对DNA甲基转移酶1(DNAmethyhransferase 1,DNMT1)基因的shRNA转染人人卵巢癌细胞系SKOV3细胞中,Western blotting检测SKOV3细胞DNMT1以及ERCC1的表达变化;利用不同浓度5-Aza-CdR于不同时间点处理卵巢癌SKOV3细胞,Western blotting检测DNMTI和ERCC1蛋白在处理前后的变化,利用亚硫酸氢钠法检测ERCC1基因启动子区域甲基化水平.结果:0.5、1.0、2.0、4.0μmol/L的5-Aza-CdR作用于SKOV3细胞后,DNMT1表达水平呈浓度依赖性降低,而ERCC1表达水平呈浓度依赖性升高;使用终浓度为1.0 μmol/L的5-Aza-CdR处理SKOV3细胞12、24、36 h后,DNMT1表达水平呈时间依赖性降低,而ERCC1表达水平呈时间依赖性升高,亚硫酸氢钠法检测示药物处理前ERCC1启动子区域处于高甲基化水平,在用1.0μmol/L的5-Aza-CdR处理后,其启动子发生了去甲基化.结论:5-Aza-CdR通过DNMT1调控卵巢癌SKOV3细胞中ERCC1基因的甲基化及其表达水平.     

Genetic polymorphisms of ERCC1 and their effects on the efficacy of cisplatin-based chemotherapy in advanced esophageal carcinoma

The aim of this study was to investigate the relationship between the ERCC1-C8092A, ERCC1-C19007T and GSTP1-A105G genetic polymorphisms and the curative effect of cisplatin-based chemotherapy in advanced esophageal carcinoma. A total of 256 pathologically confirmed advanced esophageal carcinoma patients were given regimens of cisplatin and 5-fluorouracil. Clinical evaluations were obtained from 241 patients who completed the therapy. The remission rate of patients with ERCC1-C8092A, A/C or A/A was higher compared to that of patients with C/C (51.75 vs. 29.59%, P<0.01). Progression-free survival of patients with ERCC1-C8092A, A/C or A/A was longer compared to that of patients with C/C (7.5 months vs. 4.5 months, P<0.0001). The C19007T and GSTP1-A105G genetic polymorphisms were not positively correlated with remission rates and progression-free survival of patients. In conclusion, the ERCC1-C8092A genetic polymorphism may be correlated with the efficacy of cisplatin-based chemotherapy in cases of advanced esophageal carcinoma. Further studies with a larger sample size are needed for tailored chemotherapy treatment of advanced esophageal carcinoma.     

A pooled analysis of the ERCC2 Asp312Asn polymorphism and esophageal cancer susceptibility

Published data regarding the association between the excision repair cross-complimentary group 2 (ERCC2) Asp312Asn polymorphisms and esophageal cancer susceptibility remained controversial. This meta-analysis of literatures was performed to assess the strength of association between the ERCC2 and esophageal cancer susceptibility using random effects model. We systematically searched PubMed, Embase and Web of Science with a time limit of September 15, 2013. Summary odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of association between the ERCC2 Asp312Asn polymorphism and esophageal cancer susceptibility using random effects model. A total of seven case–control studies including 1,831 cases and 2,728 controls were included for analysis. Overall, a significant association was found between ERCC2 Asp312Asn polymorphism and esophageal cancer susceptibility for GA vs. GG (OR?=?1.20, 95 % CI?=?1.03–1.40) and for the dominant model GA/AA vs. GG (OR?=?1.18, 95 % CI?=?1.03–1.35). However, the ERCC2 Asp312Asn polymorphism was a protective factor for AA vs. GA/GG (OR?=?0.63, 95 % CI?=?1.15–2.65) in esophageal squamous cell carcinoma. Our meta-analysis suggested that the ERCC2 Asp312Asn polymorphism might be associated with increased risk of esophageal adenocarcinoma and a protective factor for esophageal squamous cell carcinoma.     

ERCC1蛋白表达及其基因多态性与食管鳞状上皮细胞癌患者生存期关系

目的:研究ERCC1蛋白表达及其基因多态性与食管鳞状上皮细胞癌患者生存期关系。方法:从我院2016年1月至2017年2月时间段内肿瘤科收治的患者当中选择45例食管鳞状上皮细胞癌患者为主要研究对象，所有患者均在术后接受辅助化疗治疗，分别采用免疫组化分析和聚合酶链式反应，来研究ERCC1蛋白表达及其基因多态性与食管鳞状上皮细胞癌患者生存期关系。结果:蛋白表达阳性患者23例，生存期（29.8±2.4）个月；蛋白表达阴性22例，生存期为（30.1±2.3)个月，数据对比后分析P＞0.05，不具有统计学意义。ERCC1基因在C8092A位点上时，CC、CA、AA、患者生存时间具有统计学意义（P＜0.05）；而在C118T 位点上时，基因CC、CT和TT患者的生存时间无统计学意义(P＞0.05)。结论:ERCC1蛋白表达与患者的生存期并不存在明显联系，而在分析患者的基因多态性情况之后可看出，患者C8092A位点上的基因多态性情况与其生存期存在一定程度的关系，对关键位点进行分析较为重要。     

食管鳞癌基因多态性表达与生存分析

目的:探讨食管鳞癌肿瘤组织中ERCC1、TYMS、TUBB3基因表达与预后生存的关系。方法:选择2012年9月至2016年5月我科收治的68例食管鳞癌患者,术后病理分期IIa-IIIa期;检测肿瘤组织ERCC1、TYMS、TUBB3 mRNA表达水平。术后患者分为个体化化疗组和标准化疗组,个体化组患者根据基因检测结果选择敏感药物化疗方案（CF/DCF/TC方案）进行化疗,标准组应用CF方案化疗,所有患者长期随访,统计化疗不良反应及生存数据。结果:肿瘤组织中ERCC1、TYMS、TUBB3阳性表达率分别为43%、47%、51%,无统计学差异（P＞0.05）。所有患者总一年生存率、两年生存率及三年生存率为分别为90.57%,72.45%和59.77%。生存曲线分析提示:0项基因阳性组预后最佳（P＜0.05）,而1项、2项和3项基因阳性组间无统计学差异（P＞0.05）。个体化化疗组的III/IV级化疗不良反应发生率明显低于标准化疗组（P＜0.05）。结论:食管鳞癌患者中ERCC1、TYMS、TUBB3表达具有特定的临床特征,其高表达患者预后欠佳。根据基因检测结果进行个体化化疗可以获得更好的疗效和耐受性,不良反应更轻。     

Effect of the ERCC1 (C118T) Polymorphism on Treatment Response in Advanced Non-Small Cell Lung Cancer Patients Undergoing Platinum-Based Chemotherapy

For advanced non-small-cell lung cancer (NSCLC) cases, a platinum-based regimen is the first-line chemotherapy treatment. The excision repair cross-complementing group 1 (ERCC1) plays an important role in DNA repair and has been related to resistance to platinum chemotherapy. This study aimed to investigate the effects of the ERCC1 (C118T) polymorphism on treatment response in 26 Thai advanced NSCLC patients receiving first line platinum-based chemotherapy during January to July 2015 at King Chulalongkorn Memorial Hospital (KCMH). DNA was extracted from peripheral blood lymphocytes and the single nucleotide polymorphism of ERCC1 was genotyped using a real-time PCR method with the TaqMan assay. The distribution of C/C, C/T and T/T genotypes was 57.7 %, 34.6 % and 7.7 %, respectively. The response rate to platinum-based chemotherapy in the wild type (C/C) of ERCC1 (C118T) was better than with the variant types (C/T and T/T) but the difference was not statistically significant (29.7% vs 9.1%, P=0.274). The results showed that a genetic polymorphism in ERCC1 might influence patient response to platinum-based chemotherapy. Further multicenter studies are now required to confirm the results of our study.     

Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.

DNA repair is a critical mechanism of resistance to platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Increased ERCC1 mRNA levels are related directly to platinum resistance in various cancers. We examined the association between two polymorphisms of ERCC1, codon 118 C/T and C8092A, which are associated with altered ERCC1 mRNA levels and mRNA stability, and overall survival (OS) in 128 advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. The two polymorphisms were in linkage disequilibrium. There was a statistically significant association between the C8092A polymorphism and OS (P = 0.006, by log-rank test), with median survival times of 22.3 (C/C) and 13.4 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with poor outcome. No statistically significant association was found for the codon 118 polymorphism and OS (P = 0.41, by log-rank test), with median survival times of 19.9 (T/T), 16.1 (C/T), and 13.3 (C/C) months, respectively. In conclusion, the ERCC1 C8092A polymorphism may be a useful predictor of OS in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.     

ERCC1和XRCC3基因多态性在接受含铂方案化疗NSCLC中的疗效预测作用

[目的]探讨DNA修复基因ERCC1 118和XRCC3 241多态性对于接受一线含铂化疗方案的非小细胞肺癌（NSCLC）患者的疗效预测作用。[方法]130例晚期接受含铂化疗的NSCLC患者进入研究．应用Taqman探针结合实时荧光PCR方法分析其外周血基因多态性．分析ERCC1 118和XRCC3 241多态性与疗效、疾病进展时间和总体生存期之间的关系。[结果]130例患者的总体有效率为20％．中位生存时间为15个月．ERCC1 118和XRCC3 241多态性与疗效无显著相关性。ERCC1 118基因型C/T或T/T患者的生存时间显著延长（P=0.003）。Cox多因素分析显示,ERCC1 118基因型C/T或T/T以及化疗有效患者的生存期显著延长。[结论]DNA修复基因ERCC1 118基因型C／T或T/T多态性可以延长NSCLC患者铂类治疗后的生存时间．     

根据 ERCC1、RRM1 及 TUBB3 检测结果对食管鳞癌患者实行个体化辅助治疗的随机对照研究

目的：对食管鳞癌患者根据切除修复交叉互补基因1（ERCCl）、核糖核酸还原酶基因1（RRMl）及人微管蛋白83基因（TUBB3）mRNA在食管鳞癌组织中的表达水平选择敏感药物进行辅助化疗,评估该个体化辅助治疗方案对食管鳞癌患者预后的影响。方法：选取2011年8月-2012年8月于本院接受食管癌根治术的患者240例,病理证实均为鳞癌,分期为Ⅲ。一Ⅲ。期。将入组患者随机分为两组：对照组120例,采用顺铂（DDP）联合氟尿嘧啶（5-FU）方案进行辅助化疗;研究组120例,采用荧光定量聚合酶链反应法（FQ—PCR）对120例食管鳞癌患者肿瘤组织中ERCCl、RRMl及TUBB3mRNA表达水平进行检测,并根据三种基因mRNA表达水平选取DDP、吉西他滨（GEM）和多西他赛（DOC）等药物进行辅助化疗。对以上入组患者进行为期1年的随访,比较两组患者治疗的中位疾病进展时间（mTTP）和1年疾病复发率。结果：至随访结束,对照组和研究组分别收集数据110例和114例。对照组和研究组mTTP分别为7．3个月和10．5个月（P〈0．001）。ERCCl、RRMl及TUBB3三种基因mRNA均为高表达的患者1年内疾病复发率显著高于其他基因型组,三种基因同时高表达为疾病复发的独立危险因素（OR=2．128,P=0．039,95％CI=1．039—4．359）。结论：根据ERCCl、RRMl及TUBB3检测结果选择敏感化疗药物对食管鳞癌患者实行个体化治疗可以使患者有较大的获益,以上三种基因同时高表达是Ⅲ期食管癌复发的独立危险因素。