Mena表达及SNPs与胃癌遗传易感性及预后

  目的  探讨Mena表达与胃癌侵袭转移的相关性及SNPs与胃癌遗传易感性的关系。  方法  制作模拟胃癌侵袭转移过程的组织芯片,免疫组化染色检测Mena蛋白的表达。PCR-LDR技术检测Mena基因5个SNPs位点多态性并行测序验证。  结果  胃腺癌中Mena表达上调,肠型与混合型胃癌高于弥漫型,并与胃癌侵袭转移负相关,Mena高表达者预后好。Mena基因SNP位点rs3795443的188例对照组等位基因A、G的频率分别为91.0% 和9.0%,胃癌病例组等位基因A、G的频率为82.4% 和17.6%;AA、A/G和GG的基因型频率在对照组分别为81.9%、18.1%和0,而在病例组为68.35%、28.09% 和3.56%,差异具有统计学意义（OR=2.1489,95%CI:1.4607~3.1613,P < 0.01）。5个SNPs位点的基因型和等位基因频率与胃癌术后生存时间均无明显相关性。  结论  胃癌Mena表达升高,组织学类型的维持以及侵袭转移与其表达密切相关,高表达者预后好。Mena SNP rs3795443位点携带等位基因G的GG和A/G基因型个体的胃癌患病风险提高,提示检测该位点基因型有助于评估胃癌的遗传易感性。      

福建地区汉族人群中CLDN23基因SNPs多态性与胃癌遗传易感性及预后的相关性CSCD

目的探讨福建地区汉族人群中已知的三种claudin-23基因CLDN23单核苷酸多态性(SNPs)与胃癌遗传易感性及预后的相关性。方法应用PCR-LDR法检测CLDN23基因3个SNP位点rs12153、rs1060106 和rs11249884的基因型。结果 CLDN23基因SNP位点rs12153、rs1060106及rs11249884三个位点的基因型及等位基因频率在胃癌病例组和健康者之间差异均无统计学意义(P>0.05);胃癌病例组中三个位点的基因型分布频率与肿瘤分化程度、pT分期显著相关(P<0.05);rs12153、rs1060106的基因型分布频率与患者术后生存时间显著相关(P<0.05);CLDN23基因SNP位点rs12153、rs1060106和rs11249884两两之间未见明显的遗传连锁不平衡性;rs12153、rs1060106和rs11249884可能存在的基因单体型中,C-T-G单体型在胃癌病例组与正常对照组之间有显著差异(P<0.01)。结论福建汉族人群中,CLDN23基因SNP位点rs12153、rs1060106及rs11249884的多态性与胃癌的分化、pT分期具有相关性,可能参与胃癌的进展,rs12153、rs1060106的多态性与胃癌患者的预后有关。     

单核苷酸多态性与中国人群胃癌易感性和进展相关性的研究现状

单核苷酸多态性（SNP）是人类最常见的可遗传变异,是由个体间基因组水平的单个核苷酸变异所导致的DNA序列的多态性。作为一种新兴的遗传标记,SNP与疾病之间的关系受到了广泛关注。每个个体拥有的不同基因型决定了个体对疾病的不同易感性或对药物等的不同反应性。不同人群的SNP分布频率存在差异,如果同一人群的不同样本间可通过少量SNP位点即可反映整个群体样本主要的遗传信息,那这类SNP就可以作为标签SNP（Tag SNP）。近年来的相关研究已经证实了一些SNP位点在包括胃癌在内的多种类型肿瘤的发生发展中发挥重要作用,不同个体间或群体间的SNP差异对胃癌易感性及其进展和预后都有很大差别。本文综述了SNP、Tag SNP与胃癌的易感性及其进展的关系以及不同检测方法对结果的影响,旨在为胃癌的个体化预防和精准治疗策略提供新思路。     

p21WAF1基因多态性与胃癌易感性关系

目的:探讨p21WAF1基因缺失与多态性及其意义。方法:采用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)法和链霉菌抗生物素蛋白-过氧化酶(SP)法分别检测胃癌中p21WAF1基因缺失与多态性和p21蛋白表达。结果:PCR扩增显示,30例胃癌和45例非胃癌标本均无p21WAF1第二外显子缺失。PCR-RFLP发现胃癌和正常胃粘膜p21第二外显子多态性分别为26.7%(8/30)和8.9%(4/45),有显著性差异(P<0.05),且8例具多态性胃癌标本中的正常胃粘膜亦具有这种多态性。p21蛋白阳性表达率,胃癌为43.3%(13/30),非胃癌为100%(45/45),两者有显著性差异(P<0.05),具p21WAF1基因多态性胃癌为37.5%(3/8),与无多态性胃癌45.5%(10/22)无相关性(P>0.05)。结论:胃癌中p21WAF1基因无缺失,而存在多态性。p21WAF1基因多态性和p21表达与胃癌发生有关,但两者无相关性。WAF1     

STMN1 与胃癌的研究进展*

STMN1 为微管解聚蛋白,通过磷酸化/去磷酸化调节细胞周期,在细胞增殖分化及肿瘤的发生过程中起重要作用。在白血病及多种实体肿瘤中均有较高表达。目前国内外对STMN1 与胃癌关系的研究已初步开展。STMN1 的表达对研究胃癌的发生、发展机制及治疗具有一定意义。研究发现 STMN1 的过表达能够影响某些作用于微管的化疗药物（如多西他赛）的疗效,对指导临床用药有一定的意义。本研究对STMN 1 在胃癌发生发展中的作用、临床与预后的关系及相关调控通路在胃癌治疗中的作用进行综述。      

紧密连接蛋白claudin-1 及ZO-1 在胰腺癌中的表达*

目的：探讨紧密连接蛋白claudin- 1 及ZO- 1 在胰腺癌中的表达及在胰腺癌侵袭转移中的意义。方法：应用免疫组织化学方法检测claudin- 1 和ZO- 1 在胰腺癌不同侵袭位点（与非肿瘤胰腺组织相交界的胰腺癌侵袭前沿区、肿瘤中央区、与周围间质相交界的胰腺癌侵袭前沿区）及淋巴结转移灶和正常胰腺组织中的表达。结果：claudin- 1 与ZO- 1 蛋白正常定位于胰腺腺泡细胞和导管上皮细胞胞膜上,而在胰腺癌组织中,claudin- 1 与ZO- 1 蛋白定位从细胞膜异位至细胞浆或表达缺失,重度异位表达率分别为66.7% 和69.2% 。在与非肿瘤胰腺组织相交界处的胰腺癌组织中,低- 未分化胰腺癌的claudin- 1 重度异位表达率（91.7%）明显高于高- 中分化胰腺癌（55.6% ,P<0.05）;与周围间质相交界处的胰腺癌侵袭前沿区claudin- 1 重度异位表达率（89.7%）高于与非肿瘤胰腺组织相交界处的胰腺癌侵袭前沿区（66.7% ,P<0.05）;淋巴结转移灶重度异位表达率最高（92.3% ,P<0.05）。 同样与周围间质相交界处的胰腺癌侵袭前沿区ZO- 1 重度异位表达率（94.9%）也高于与非肿瘤胰腺组织相交界处的胰腺癌侵袭前沿区（64.2% ,P<0.05）,淋巴结转移灶最高（100% ,P<0.05）;原发胰腺癌组织各个位点中claudin- 1 与ZO- 1 表达呈正相关关系。结论：claudin- 1 和ZO- 1 异位表达对胰腺癌的发生起促进作用;claudin- 1 异位表达与胰腺癌的分化有关;claudin- 1 和ZO- 1 异位表达率增加促进胰腺癌的侵袭与转移。     

代谢酶基因多态性与胃癌遗传易感性

肿瘤遗传易感性是目前国内外极其关注的研究领域，不同个体对环境致癌物代谢能力的差异决定了个体对肿瘤的易感性。化学致癌物大多为间接致癌物，需经代谢活化后与细胞生物大分子作用而致癌，经解毒酶作用而失活。毒物代谢过程主要包括两类酶：Ⅰ相酶介导氧化代谢，具有活化作用(包括CYP家族)，Ⅱ相酶具有解毒效应(包括GSTs、     

SRC1在胃癌中的表达及其与预后的关系

目的 探讨类固醇受体辅助活化因子-1(Steroid receptor coactivator 1,SRC1)蛋白在胃癌组织中的表达及其与患者临床病理参数和预后的相关性。方法 收集36例胃癌组织及其配对的癌旁组织,qRT-PCR法及Western blot法检测SRC1mRNA和蛋白的表达水平。应用免疫组化方法检测286例胃癌组织中SRC1蛋白的表达情况,分析SRC1蛋白表达与胃癌临床病理参数的关系及其对患者预后的影响。结果 与癌旁组织相比,胃癌组织中SRC1mRNA表达水平明显降低(P=0.004),SRC1蛋白表达水平也明显降低。SRC1蛋白的表达强度与胃癌患者临床病理参数无显著关系。Kaplan-Meier生存曲线分析发现高表达SRC1组5年生存率显著高于低表达组(P=0.009)。Cox回归分析结果显示低表达SRC1(P=0.002)、肿瘤侵袭T_4a~T_4b(P=0.004)、淋巴结转移N(P=0.038)、远处转移M1(P＜0.001)是独立影响总生存时间的预后不良因素。SRC1低表达较高表达患者预后差。结论 胃癌中SRC1的表达明显降低,胃癌组织中的SRC1表达水平可作为独立的胃癌预后不良因素,其过低表达与胃癌的发展密切相关,可能作为一个抑癌基因及判断胃癌患者预后的标志物。     

染色体1q22区域遗传变异影响胃癌易感性的生物学机制研究

  目的  探索染色体1q22区域易感基因在胃癌发生中的作用和机制。  方法  基于genotype-tissue expression（GTEx）数据库,鉴定候选易感基因;通过人群样本进行基因差异表达分析,并通过细胞和动物实验探究易感基因在胃癌发生中的作用;通过全转录组测序探究候选易感基因在胃癌发生中参与的下游通路和机制。  结果  表达数量性状基因座（expression quantitative trait loci,eQTL）分析证实rs760077基因型与THBS3、GBA和GBAP1基因的表达水平均显著相关（P值分别为1.20×10-21,1.80×10-4和3.49×10-17）。差异表达分析和功能学实验证实GBAP1在胃癌组织中呈现高表达状态,并且敲低GBAP1后能够显著抑制胃癌细胞增殖能力。全转录组测序表明GBAP1能够影响PHGDH、PSAT1和PSPH基因的表达水平并参与包括甘氨酸、丝氨酸、苏氨酸代谢和一碳代谢在内的多种代谢通路。  结论  本研究证实1q22区域的遗传变异可以通过调控促癌基因GBAP1的表达,影响氨基酸合成代谢通路关键酶基因PHGDH、PSAT1和PSPH的表达,从而促进胃癌的发生。      

胃癌患者紧密连接蛋白1的表达及意义

[目的]研究胃癌组织中紧密连接蛋白1(ZO-1)的表达及意义。[方法]采用免疫组织化学方法检测辽宁省肿瘤医院2001年1月~2006年12月期间收集的50例正常胃组织和100例胃癌及其癌旁组织标本中ZO-1表达情况,并分析胃癌组织中ZO-1表达水平与各临床参数之间的关系。[结果]ZO-1在胃癌组织中表达下调,在胃癌组织中的表达率(40.0%)显著低于癌旁组织(84.0%)和正常胃组织(84.0%)(P=0.000)。ZO-1表达水平与胃癌患者年龄、性别和组织学类型无关(P均>0.05)。ZO-1表达水平与分化程度、浸润深度、区域淋巴结转移、远处转移及临床分期具有相关性,分化程度越低、浸润越深、伴有淋巴结转移和远处转移、临床分期越高,ZO-1表达水平越低(P均<0.05)。ZO-1高表达组5年生存率高于低表达组(70%vs20%,P<0.05)。[结论]ZO-1在胃癌组织中表达下调,与肿瘤的临床分期、转移和预后密切相关,可作为胃癌诊断和预后评价的标志物之一。     

非小细胞肺癌组织中ZO-1的表达及其临床意义

背景与目的 已有的研究表明紧密连接蛋白-1(zonula occluden-1,ZO-1)表达和肿瘤细胞的生长和转移存在密切联系.本研究旨在探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)组织中ZO-1表达的临床意义.方法 应用实时荧光定量PCR、Western blot和免疫组化检...     

谷胱甘肽转移酶M1基因多态与胃癌易感性关系的Meta分析

[目的]探讨谷胱甘肽转移酶M1(GSTM1)基因多态性与胃癌易感性关系。[方法]检索并筛检1996￣2007年间GSTM1基因多态性与胃癌易感性关系相关的文献,利用RevMan4.28和SAS9.1.3软件包对各研究结果进行异质性分析,选择适当的分析模型进行定量合并估计其效应,同时进行稳定性的分析和发表偏倚的估计。[结果]共纳入28篇文献3776例胃癌病例和7772例对照;Meta分析结果显示,携带GSTM1空白基因型者胃癌的发病风险是非携带者的1.26倍(95%CI:1.11￣1.43),按不同人群分层分析显示亚洲人群特别是中国人群GSTM1基因多态性与胃癌的发病风险显著相关(亚洲:OR=1.39,95%CI:1.20￣1.60;中国:OR=1.58,95%CI:1.35￣1.85),而在高加索人群中则无明显关联(OR=1.01,95%CI:0.83￣1.22)。敏感性分析显示该结果较为稳定,但存在显著性发表偏倚。[结论]GSTM1空白基因型是亚洲人群,特别是中国人群胃癌发病的危险因素。     

CYP2E1基因多态性与肺癌易感性关系的研究进展

肺癌是最常见的恶性肿瘤,其发生发展与吸烟、大气污染、危险因素暴露及基因变异等多种因素有关,由细胞色素P450(CYP450)基因家族所编码的细胞色素P450酶系(Cytochrome P450s)所组成的Ⅰ相酶介导氧化代谢,具有重要的解毒功能.CYP2E1是CYP450基因家族重要成员之一,大量研究表明其基因多态性与肺癌易感性密切相关,但研究结果不一致.     

Interleukin-10 Polymorphisms, Cancer Susceptibility and Prognosis

Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions and may have both tumour-promoting and -inhibiting properties. A large number of polymorphisms (primarily single nucleotide polymorphisms (SNPs)) have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms are associated with differential expression of IL-10 in vitro and in some cases in vivo has been obtained and a number of studies have investigated associations between IL-10 polymorphisms and cancer susceptibility/prognosis. The results from 22 studies in 13 different malignancies are reviewed. In 17 of these studies, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were reported. In some of these cancers genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others genotypes associated with high IL-10 expression were a risk factor. Published findings in breast cancer are as yet conflicting. Most, but not all of the studies reviewed are based on small sample sizes and a limited number of IL-10 polymorphisms. However, the preliminary data obtained thus far indicate that larger studies are required in a number of cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and combine genotype and gene expression studies in the same subjects. Such studies will contribute significantly to our understanding of the biological role of IL-10 in cancer development.     

VEGF的SNP状态预测贝伐株单抗治疗转移性结直肠癌的长期疗效

目的 检测转移性结直肠癌患者外周血血管内皮生长因子(VEGF)单核苷酸多态性(SNP),探讨VEGF的SNP与患者预后的关系.方法 60例转移性结直肠癌患者的外周血样本,均接受过标准的化疗,其中20例加用了贝伐珠单抗,应用MassARRAY方法,成功进行9个VEGF的SNP的检测,包括-2578C＞A、-460T＞C、-1455T＞C、-1154G＞A、-634G＞C、-398G＞A、-497T＞C、-2455 ＞-T、-936C＞T.结果 60例转移性结直肠癌患者,联合靶向治疗组的总生存期优于单用化疗组(P=0.01),VEGF各SNP变异率与NDBI数据库相似,-1455T＞C变异率极低,无临床价值;-2578C＞A和-460C＞T变异具有较高一致性;入组患者中SNP-497TT纯合子患者总生存期劣于其他患者(P=0.02);应用贝伐株单抗患者,SNP-497 3种基因型总生存期均有明显差异(P=0.01),SNP-398AA纯合变异者总生存期优于其他患者(P=0.02)SNP-2455 CC纯合子者总生存期优于其他患者(P=0.01).结论 在转移性结直肠癌,外周血VEGF的SNP状态与贝伐珠单抗以及化疗的长期疗效可能相关,需要进一步增加病例,加强这方面的研究.     

Associations of ABCB1 and XPC Genetic Polymorphisms with Susceptibility to Colorectal Cancer and Therapeutic Prognosis in a Chinese Population

Associations between ABCB1 and XPC genetic polymorphisms and risk of developing colorectal cancer (CRC)as well as clinical outcomes in CRCs with chemotherapy were investigated. A case-control study was performedon the ABCB1 C3435T, G2677T/A and XPC Lys939Gln polymorphisms in 428 CRC cases and 450 hospitalbased,age and sex frequency-matched controls using polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) assays. We observed that the ABCB1 3435CT or CC+CT variants were significantlylinked with increasing risk of developing CRC (adjusted OR (95% CI): 1.814 (1.237-2.660), P=0.0022; adjustedOR (95% CI): 1.605 (1.117-2.306), P=0.0102, respectively). Moreover, the distribution frequency of XPC ACgenotype or AC+CC genotypes also showed a tendency towards increasing the suscepbility for CRC (P=0.0759and P=0.0903, respectively). Kaplan-Meier curves showed that the ABCB1 C3435T variant was associated witha tendency toward longer progression-free survival (PFS) (n=343, Log-rank test: P=0.063), and the G2677T/Avariant genotypes (GT+TT+GA+AA) with a tendency for longer OS in postoperative oxaliplatin-based patients(n=343, Log-rank test: P=0.082). However, no correlation of the XPC Lys939Gln polymorphism was found withPFS and OS in patients with postoperative oxaliplatin-based chemotherapy (n=343). Our study indicated thatABCB1 polymorphisms might be candidate pharmacogenomic factors for the prediction of CRC susceptibility,but not for prognosis with oxaliplatin chemosensitivity in CRC patients.     

Effects of p53 Codon 72 and MDM2 SNP309 Polymorphisms on Gastric Cancer Risk among the Iranian Population

Background: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. Materials and Methods: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR(AS-PCR). Results: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). Conclusions: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.     

Different Expression of Occludin and ZO-1 in Primary and Metastatic Liver Tumors

Tight junction (TJ) components were found to be correlated with carcinogenesis and tumor development. TJs are composed of three main integral membrane proteins; occludin, claudins and JAMs. Alteration of the TJ protein expression may play an important role in the process of cell dissociation, which is among the first steps of tumor invasion and metastasis. Reduced expression of ZO-1 has been reported to be associated with invasion of several tumors. The aim of the present study was to detect differences between occludin and ZO-1 expression in normal liver samples, HCCs and colorectal liver metastases. Expression of occludin and ZO-1 was analysed in 25 surgically removed human hepatocellular carcinomas (HCC) and 25 human colorectal liver metastases. Gene expression levels were measured by real-time RT PCR, protein expression was determined by immunohistochemistry, comparing tumors with the surrounding nontumorous parenchyma and with seven normal liver samples. Occludin and ZO-1 mRNAs showed significant downregulation in HCCs in comparison with normal liver and were also downregulated in the metastases when compared with normal liver. Occludin and ZO-1 proteins were weakly expressed on hepatocytes in normal liver, while strong expression was found on bile canaliculi. In HCCs occludin and ZO-1 did not show immunopositivity on tumor cells, while colorectal metastatic tumors revealed high levels of these molecules. HCCs and metastases are characterized by markedly different protein expression pattern of occludin and ZO-1, which phenomenon might be attributed to the different histogenesis of these tumors.