MKK4基因启动子区-1304T〉G多态与食管癌易感性研究

目的：探讨MKK4基因-1304T〉G位点单核苷酸多态基因型在中国东部人群中的分布及其对食管癌易感性的影响。方法：设计以医院为基础的病例对照研究,进行食管癌患者与对照人群频数匹配,采用聚合酶链反应-限制性片段长度多态性的方法（PCR-RFLP）对571例食管癌患者和785名正常人的MKK4基因-1304T〉G位点（rs3826392）进行基因分型。利用Logistic回归分析基因多态性与食管癌发病风险的关联,并校正年龄和性别。结果：MKK4基因-1304T〉G位点基因多态性在病例和对照组中分布差异无统计学意义,GG基因型（OR=0.98,95%CI：0.67～1.61）,TG基因型（OR=1.12,95%CI：0.90～1.43）,P=0.435。结论：MKK4基因-1304T〉G位点的单核苷酸多态可能与中国东部人群食管癌易感性无关。     

TRAIL-DR4启动子区基因多态性与肺癌易感性的相关性研究

[目的]初步探讨TRAIL死亡受体4（DR4）基因多态性与肺癌易感性的关系。[方法]采用PCR-RFLP技术,对92例肺癌患者和92例健康对照者的DR4基因启动子区的-972C/T和-397G/T多态性位点基因型进行检测。以非条件Logistic回归校正混杂因素进行相关性分析。[结果]TRAIL-DR4基因-972C/T位点多态性与肺癌易感性无明显相关性;在吸烟≥20年的人群中含有-397G/T位点T等位基因（GT＋TT）比GG纯合基因型的肺癌发病风险增加（OR=3.462,95%CI：1.222～9.811,P=0.019）。[结论]DR4基因多态性与肺癌的易感性间存在一定的关系。     

MKK4与肿瘤研究现状

MKK4是丝裂原活化蛋白激酶MAPKK家族的一个成员,位于MAPK通路的重要位置,能同时磷酸化并激活下游两条p38和JNK通路,最终活化转录因子,引起一系列复杂的生物学反应。研究发现,MKK4与不同类型肿瘤的发生、发展、恶性转移密切相关,且作用机制复杂。     

DNA 修复酶基因多态性与食管癌易感性的关系

癌症的形成不但与癌基因激活、抑癌基因失活、代谢酶基因异常等有关,而且与修复酶基因异常也有重要关系。目前许多研究致力于寻找食管癌的易感基因,从而阐明食管癌的遗传易感性及癌变机制。本文就食管癌相关 DNA 修复基因的研究现状作一综述。     

MKK4与肿瘤关系的研究进展

目的:探讨MKK4基因与肿瘤关系的研究进展.方法:以MKK4和肿瘤为关键词,检索1989-2008年PubMed全文数据库和维普资讯-中国科技期刊数据库.纳入标准:1)MKK4基因结构及生物学特性的研究;2)MKK4与肿瘤发生发展关系的研究.粗选有76篇关于MKK4结构特点及其与肿瘤关系研究文章,根据纳入标准,精选45篇文献,最后纳入分析27篇文献.结果:MKK4是MAPK信号转导通路的组成部分,能磷酸化并激活JNK通路和p38通路,将细胞外刺激信号转导至细胞及其核内,引起细胞的增殖、分化、转化及凋亡等生物学反应.MKK4在肿瘤的形成发展过程中具有重要作用,有研究证实MKK4为肿瘤转移抑制基因或抑癌基因,对肿瘤有抑制作用.然而,也有研究证实MKK4为癌基因,有致肿瘤作用.结论:到目前为止,MKK4与肿瘤关系还存在许多争议,需要我们进一步时其进行认识.     

MCP-1基因多态性与食管癌易感性的关系

目的：研究 MCP-1-2518位点基因多态性与济南地区汉族食管鳞状细胞癌（esophageal squamous cell carcinoma,ESCC）易感性的关系。方法应用聚合酶链反应（PCR）和 DNA 直接测序方法对202例 ESCC 患者和265例健康对照进行 MCP-1-2518位点基因多态性检测。结果ESCC 患者 MCP-1-2518位点的多态性基因型和等位基因分布与健康对照组差异无统计学意义,P ＞0．05。根据吸烟状况的分层分析发现,与 GG 基因型相比,携带 AA 基因型可显著增加吸烟者的 ESCC 发病风险,经性别和年龄校正的 OR 值为3．064,95％CI 为1．397～6．718;而在非吸烟的患者和健康对照组之间差异无统计学意义,P ＞0．05。结论MCP-1-2518位点的多态性基因型和等位基因不单独影响 ESCC 的发生和发展, MCP-1-2518位点的 AA 基因型可增加吸烟人群 ESCC 易感性。     

雄激素受体基因微卫星CAG多态与食管癌的分级

目的:探讨食管癌组织中雄性激素受体(AR)基因外显子1微卫星位点(CAG)n的多态性与食管癌分级的关系,及其与肿瘤生物学特性的相关性。方法:应用PCR扩增方法,对41例食管癌组织和30例癌旁组织AR的第一外显子CAG微卫星数量进行测定,并进行不同级别间的比较分析。结果:食管癌组织AR基因(CAG)n重复范围8～28,癌旁组织n范围在8～24;食管癌组织n范围在≤10或≥22的占34.1%,比癌旁组织高(13.3%),经χ²检验有显著性差异;在29对配对的标本中,多态性发生改变的占48.3%;AR基因CAG微卫星的数量随着食管癌细胞分化程度的降低而减少,其低分化食管癌(13.6)均数低于高分化食管癌(17.5),短组AR基因CAG微卫星分布比例随着食管癌的分化程度的升高而降低,长组AR基因CAG微卫星分布比例随着食管癌的分化程度的升高而增加。结论:在食管癌组织AR基因(CAG)n重复多态的改变是高发事件,AR基因的(CAG)n微卫星数量的减少与食管癌的恶性程度相关。     

CTLA-4基因多态性与肾癌易感性的相关性研究

目的 探讨CTLA-4基因rs5742909、rs231775位点单核苷酸多态性与中国汉族人群肾癌易感性的关系.方法 收集96例肾癌患者和96名健康对照人群的基线资料,采集研究对象5 ml外周血用于提取全血DNA,应用im-LDR技术对rs5742909、rs231775位点进行基因分型,观察其基因型在病例组和对照组之...     

NQO1基因多态性与客家人群食管癌易感性关系的探讨

目的:通过对醌氧化还原酶（NQO1）基因多态性与客家人群食管癌遗传易感性关系的研究,探讨遗传因素在该人群食管癌发病中的作用。方法:采取病例-对照分子流行病的研究方法,选择经病理检查确诊后的梅州地区客家人群122例食管癌患者(食管癌组)和同时期123例正常对照人群（正常对照组）,对NQO1基因rs1800566、rs10517、rs1437135共3个位点进行基因型及等位基因检测,分析其在两组间的分布特征。结果:NQO1基因3个位点在梅州地区客家人群中均存在多态性的改变,但两组的基因型和等位基因分布频率差异均无统计学意义（P>0.05）。经性别、年龄分层分析结果显示也无显著性差异。同时对影响食管癌发生的多种因素研究显示,吸烟、饮酒、经常食用腌制食品、喜热烫饮食以及有消化道肿瘤家族史与食管癌发病呈正相关,其中,有消化道肿瘤家族史可能是该地区人群发生食管癌的最危险因素。结论:NQO1基因rs1800566、rs10517和rs1437135位点多态性可能与客家人群食管癌的易感性无关,而环境因素中饮酒、吸烟、常食腌制食品等可能是该地区食管癌发病的危险因素。     

MTHFR基因遗传多态与食管癌贲门癌易感性的关系

目的:探讨食管癌高发区亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态与食管癌、贲门癌发病风险的关系。方法:以聚合酶链反应和限制性片段长度多态方法,分析584例食管癌患者、467例贲门癌患者和540例正常对照的MTHFR基因C677T基因型及其与食管癌、贲门癌发病风险的相关性。结果:在正常对照中,MTH-FR677CC、CT、TT基因型频率分别为22.1%、43.3%和34.6%,在食管癌患者中分别为12.5%、45.0%和42.5%(P=0.000);在贲门癌患者中分别为15.8%、43.5%和40.7%(P=0.024)。多因素分析发现,携带677TT基因型和677CT基因型的个体发生食管癌的风险分别是677CC基因型的2.36倍和1.76倍,发生贲门癌的风险分别是1.34倍和1.23倍。结论:MTHFR单核苷酸多态是食管癌高发区食管癌和贲门癌的遗传易感性因素。     

The association between −1304T>G polymorphism in the promoter of MKK4 gene and the risk of sporadic colorectal cancer in southern Chinese population

MKK4 (mitogen‐activated protein kinase kinase 4, NM_003010.2), which belongs to the mitogen‐activated protein kinase pathways, possesses functions in tumorigenesis. We hypothesized the genetic variants in MKK4 gene may alter its functions and thus cancer risk. In current hospital‐based case‐control study of 706 patients with sporadic colorectal cancer (CRC) and 723 sex‐age–frequency‐matched control subjects in a southern Chinese population, we genotyped two polymorphisms of MKK4 promoter (i.e., ?1304T>G, rs3826392 and ?1044A>T, rs3809728) and assessed their associations with the risk of sporadic CRC. Compared with ?1304TT genotypes, ?1304TG had a significantly decreased risk of CRC (adjusted odds ratios [OR] = 0.56; 95% CI = 0.44–0.72; p = 3.53 × 10^?6), the ?1304GG carriers had a further decreased risk of CRC (OR = 0.40; 95% CI = 0.23–0.70; p = 1.32 × 10^?3), and there was a significant trend for an allele dose effect on risk of CRC (p_trend = 2.64 × 10^?7). The decreased risk associated with ?1304G variant genotypes (i.e., TG+GG) was more pronounced in the subjects older than 60 years (adjusted OR = 0.41; 95% CI = 0.29–0.57; p = 2.25 × 10^?7), in ever drinkers (adjusted OR = 0.41; 95% CI = 0.28–0.59; p = 2.42 × 10^?6). The age and alcohol drinking status interacted with ?1304G variant genotypes on reducing cancer risk (p values for interaction were 0.015 and 0.043, respectively). Western blotting analysis showed that the levels of Mkk4 protein in sporadic CRC neoplastic tissues were significantly higher in the carriers of ?1304G variant genotypes than that in those with ?1304TT genotypes. However, no significant association was observed between ?1044A>T polymorphism and risk of CRC. To the best of our knowledge, this is the first study of genetic variants in MKK4 and cancer susceptibility. Larger studies are needed to validate our findings. © 2009 UICC     

The protective role of polymorphism MKK4-1304 T>G in nasopharyngeal carcinoma is modulated by Epstein-Barr virus' infection status

MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein-Barr Virus (EBV)-induced c-Jun N-terminal kinase (JNK) activation. Functional polymorphism MKK4 -1304T>G has been showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, -1304T>G and -1044A>T were genotyped in two independent case-control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common -1304TT genotype, carriers of variant genotypes (-1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67-0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41-0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88-1.26), and that the -1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the -1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 -1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 -1304 T>G interaction as a causative factor for the NPC.     

MKK4基因在喉鳞癌中的表达及其临床意义

目的:研究丝裂原活化蛋白激酶激酶4 (mitogen-activated protein kinase kinase 4,MKK4)在喉鳞状细胞癌组织中的表达及其临床意义.方法:应用RT-PCR和免疫组织化学方法检测42例喉鳞癌、20例喉乳头状瘤及20例声带息肉组织中MKK4 mRNA和蛋白的表达,分析其与喉鳞癌临床病理参数之间的关系.结果:MKK4 mRNA和蛋白表达的阳性率在喉鳞癌、喉乳头状瘤及声带息肉组织中逐渐降低,且差异有统计学意义(P＜0.05).MKK4 mRNA和蛋白的表达随喉鳞癌的浸润深度增加而上升(P＜0.05),在有淋巴结转移组中的表达高于无淋巴结转移组(P＜0.05),在临床Ⅲ～Ⅳ期患者中的表达高于临床Ⅰ～Ⅱ期的患者(P＜0.05).MKK4的表达与患者的年龄、性别、肿瘤发生部位及组织学分级无相关性(P＞0.05).结论:MKK4 mRNA和蛋白在喉鳞癌组织中的表达上调可能与喉鳞癌的发生及浸润转移有关,MKK4可能成为一个潜在的判断喉鳞癌发生与转移的观测指标.     

人食管癌相关基因4在食管癌细胞系EC9706中表达缺失的机制

目的 探讨人食管癌相关基因4(ECRG4)在食管癌中表达缺失的机制.方法 采用聚 合酶链反应-单链构象多态(PCR-SSCP)和DNA测序的方法检测80对配对食管鳞状细胞癌(ESCC)肿瘤组织和癌旁正常上皮中ECRG4的外显子突变;采用DNA亚硫酸氧盐修饰和序列特异性聚合酶链反应(ssPCR)检测EC9706细胞系ECRG4基因启动子CpG岛甲基化状态;采用逆转录聚合酶链反应(RT-PCR)检测去甲基化药物5-氮杂-2-脱氧胞苷或三氧化二砷(As2O3)处理后ECRG4 mRNA的重新表达.结果 80对ESCC配对标本中,ECRG4的4个外显子编码区均未发现突变.EC9706细胞系ECRG4基因核心启动子区16个CpG岛中,有11个呈高甲基化状态,ECRG4 mRNA不表达.EC9706细胞处理前ECRG4 mRNA不表达,去甲基化药物处理后,ECRG4 mRNA均重新表达.结论 甲基化表观遗传学机制是导致ECRG4基因在食管癌细胞系EC9706中表达缺失的一个机制.

Abstract：

Objective To investigate the mechanism of loss of human esophageal cancer-related gene 4 (ECRG4) expression in esophageal squamous cell carcinoma (ESCC.) Methods PCR-SSCP and DNA sequencing analysis were used to detect the mutation of ECRG4 exons in esophageal cancer and matched adjacent normal tissues of 80 patients. DNA bisulfite-modifying ssPCR sequencing assay was used to examine the methylation status of ECRG4 promoter in human esophageal squamous cell carcinoma EC9706 cells. The re-expression of ECRG4 mRNA was examined by RT-PCR in EC9706 cells, after treatment with either demethylation drug 5-aza-2'-deoxycytidine or arsenic trioxide. Results No mutation in the four ECRG4 exons was found in all the ESCC and matched normal adjacent tissues. RT-PCR showed that 11 of 16 CpG islands of ECRG4 promoter were hypermethylated, while ECRG4 mRNA expression level was undetectable in the EC9706 cells. The ECRG4 mRNA was re-expressed after treatment with either demethylation drug 5-aza-2'-deoxycytidine or arsenic trioxide. Conclusion The epigenetic mechanism of methylation is a reason of loss of ECRG4 gene expression in the ESCC cell line EC9706.     

MKK4基因启动子区遗传变异与中国南方人群肺癌易感性的相关性研究

目的:探讨丝裂原活化蛋白激酶激酶4(mitogen-activated protein kinase kinase4,MKK4)基因启动子区单核苷酸多态性与中国南方人群肺癌发病风险的关系。方法:采用病例对照研究方法,收集800例肺癌病例和900例正常对照,采用TaqMan技术检测MKK4基因启动子区多态位点rs3826392(-1304T>G)的基因型。应用SAS9.3软件分析其与肺癌易感性的相关性。结果:MKK4基因启动子区-1304T>G基因型在对照组中的频率分布符合Hardy-Weinberg平衡(P=0.149),其在病例组和对照组的分布差异有统计学意义(P=0.001);与携带TT基因型个体相比,携带TG杂合子的个体患肺癌的风险下降25%[校正比值比(oddratio,OR)=0.75,95%可信区间(confidence interval,CI)=0.58～0.97],而携带GG变异纯合子者患肺癌的风险下降45%(校正OR=0.55,95%CI=0.33～0.94);随着变异型等位基因G的个数增加,肺癌发病风险逐步降低(P趋势<0.001)。结论:MKK4基因启动子区-1304T>G基因遗传变异可能降低肺癌发病风险。     

Relationship between LAPTM4B gene polymorphism and susceptibility of colorectal and esophageal cancers.

BACKGROUND: Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is a novel gene of the mammalian LAPTM family and has been shown to be overexpressed in human hepatocellular carcinoma. There are two alleles, LAPTM4B*1 and *2, which share the same sequence except for one segment of 19 bp in the 5' untranslated region of the exon 1. LAPTM4B*1 has one 19 bp segment, while LAPTM4B*2 has two tight tandem segments. The current case-control study was aimed to identify relationship between the gene polymorphism of LAPTM4B and the susceptibility of colorectal and esophageal cancers. PATIENTS AND METHODS: Blood samples were collected from patients with colon, rectal or esophageal cancers and control subjects. Genotypes of LAPTM4B were determined by PCR to detect differences between cancer cases (n = 701) and healthy controls (n = 350). Association between the LAPTM4B polymorphism and the risk of cancer was calculated by unconditional logistic regression models. RESULTS: We found that there was a significant difference (P = 0.0016) in allelic frequencies of LAPTM4B*2 between colon cancer cases (33.2%) and controls (24.1%). The risk of colon cancer was elevated significantly in cases with *1/2 genotype [odds ratio (OR) = 1.474; 95% confidence interval (CI) = 1.037-2.095] and *2/2 genotype (OR = 2.531; 95% CI = 1.316-4.868) when compared with the *1/1 genotype. No significant difference was observed for LAPTM4B*2 between the rectal or esophageal cancer cases when compared with the controls. The polymorphism in LAPTM4B was associated with increased risk of colon cancer but not of rectal and esophageal cancers. CONCLUSIONS: These results indicate that the genetic polymorphism of LAPTM4B is a potential risk factor for the development of colon cancer.     

雌激素受体基因ESR1多态性与乳腺癌易感性的关系

目的：研究雌激素受体α（ESR1）基因单核苷酸多态性（SNPs）与乳腺癌易感性的关系。方法：运用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）分析的方法检测193例中国汉族女性乳腺癌患者和71名正常女性对照者ESR1基因上rs11155816位点的基因型,以SPSS 11.0软件卡方检验处理数据。结果：rs11155816位点等位基因频率符合Hardy-Weinberg遗传平衡定律。rs11155816位点的等位基因及基因型与患者肿瘤位置及是否存在远处转移相关,差异有显著性（P〈0.05）;与年龄、大小、组织学类型、受体表达无关。rs11155816位点等位基因及基因型频率在乳腺癌人群与正常对照者间分布差异有显著性,乳腺癌人群中等位基因A频率高于正常人群（23.8%比15.5%,P〈0.05）。结论：rs11155816位点基因的多态性与乳腺癌患者的肿瘤位置和远处转移相关,等位基因A携带者乳腺癌发病风险较高。     

细胞毒性T淋巴细胞相关抗原4编码区49位点的基因多态性与宫颈癌遗传易感性的关系

目的 探讨细胞毒性T淋巴细胞相关抗原4(CTLA-4)编码区49位点的基因多态性与宫颈癌遗传易感性的关系。方法 收集314例宫颈癌患者和320例正常对照者的外周静脉血标本,应用聚合酶链反应-限制性片段长度多态性法,检测CTLA-4 +49 A/G多态位点的基因型。采用多因素Logistic回归法,分析基因多态性与官颈癌发病风险的相关性以及与宫颈癌临床病理特征的关系。结果病例组中CTLA-4 +49 A等位基因和AA基因型的频率分别为32.5％和9.6％,对照组中分别为25.8％和5.6％。携带CTLA-4 +49 AA基因型者患宫颈癌的风险是GG基因型的2.06倍(95％ CI 为1.10～ 3.85,P＝0.024)。CTLA-4 +49基因多态与官颈癌临床分期、病理类型、分化程度、肿瘤大小和血清鳞状上皮细胞癌抗原水平等临床病理因素均无关（均P ＞0.05）。结论CTLA-4基因有可能是宫颈癌的遗传易感基因。