乙醇脱氢酶2和乙醛脱氢酶2基因多态性及饮酒习惯与直肠癌易感性的研究

目的:研究乙醇脱氢酶2(ADH2)、乙醛脱氢酶2(ALDH2)基因多态性与直肠癌易感性的关系。方法:采用病例-对照研究方法,以PCR-DH-PLC检测研究对象的ADH2/ALDH2基因型,比较不同的基因型及生活习惯与直肠癌的关系。结果:1)与不饮酒者相比较,饮酒者患直肠癌的危险性显著增高(OR=2.20,95%CI:1.47～3.28,P=0.000);2)多因素分析结果未发现ADH2、ALDH2各基因型与直肠癌的危险性有关。3)对ADH2、ALDH2基因多态相互作用的分层分析发现,同时携带ADH2A/A和ALDH2G/G基因型者,发生直肠癌的危险性显著增高(性别、年龄和吸烟调整OR=1.82,95%CI:1.07～3.09)。4)在饮酒者中,ADH2A/A、A/G G/G基因型者患直肠癌的调整OR分别为2.56(95%CI:1.38～4.73)和2.10(95%CI:1.15～3.84);ALDH2G/G基因型者发生直肠癌的调整OR为1.82(95%CI:1.07～3.09)。结论:饮酒是直肠癌的危险因素;ADH2A/A与ALDH2G/G基因型在增加直肠癌易感性上有协同作用;ALDH2G/A A/A基因型可减弱饮酒患直肠癌的危险性。     

乙醛脱氢酶2基因多态性和饮酒习惯与肝癌、胃癌、食管癌的易感性

目的：研究乙醛脱氢酶2（ALDH2）基因多态性和饮酒习惯与肝癌、胃癌和食管癌的易感性。方法：88例肝癌以性别、年龄和居住地与对照按1：1配对；104例胃癌和98例食管癌选择同一组（235例）非肿瘤居民为对照，用PCR－RFLP方法检测研究对象的ALDH2基因型。结果：肝癌、胃癌、食管癌病例与对照组中ALDH2变异基因型携带者分别占36．36％和35．23％、47．12％和45．36％、32．65％和45．36％，差异无显著性。在携带ALDH2变异基因型的饮酒人中，每月饮酒总量＞3kg者发生肝癌的危险性是≤3kg者的7．2倍，并存在显著的剂量效应关系。在携带ALDH2谷氨酸纯合型的男性中，饮酒者发生癌的危险性是不饮酒者的2．69倍。结论：该研究揭示了携带ALDH2变异基因型者大量饮酒将显著增加患肝癌的危险性。     

乙醇和乙醛脱氢酶基因多态与男性结直肠癌的易感性

目的研究乙醇脱氢酶2(ADH2)和乙醛脱氢酶2(ALDH2)基因多态及饮酒习惯与男性结直肠癌易感性的关系。方法在江苏省进行了一项病例-对照研究(结直肠癌患者190例,人群对照222名),调查研究对象的生活习惯,抽取静脉血,提取白细胞DNA,采用聚合酶链反应(PCR)和变性高效液相色谱法(DHPLC)检测研究对象的ADH2Arg47His(G-A)和ALDH2Glu487Lys(G-A)的基因型。结果①ADH2A/A和ALDH2G/G基因型显著增加结直肠癌的易感性。在调整了年龄和吸烟状况后,ADH2A/A基因型者与携带G等位基因者相比,发生结直肠癌的危险性上升到1.61(95%CI:1.09~2.38);ALDH2G/G基因型者与携带A等位基因者相比,发生结直肠癌的危险性上升到1.79(95%CI:1.19~2.69)。②与ADH2G和ALDH2A等位基因携带者相比,同时携带ADH2A/A和ALDH2G/G基因型者发生结直肠癌的OR值上升到3.05(95%CI:1.67~5.57);与不饮酒的ADH2G等位基因携带者相比,拥有ADH2A/A基因型的饮酒者的OR值上升到3.44(95%CI:1.84~6.42);与不饮酒的ALDH2A等位基因携带者相比,拥有AL-DH2G/G基因型的饮酒者的OR值上升到2.70(95%CI:1.57~4.66)。结论ADH2和ALDH2基因多态性与男性结直肠癌的易感性相关。ADH2,ALDH2基因多态之间以及基因多态与饮酒习惯之间,在结直肠癌发生中存在显著的协同作用。     

饮酒增加广西乙醛脱氢酶2 基因变异基因型携带者发生肝癌的危险性

 目的 研究乙醛脱氢酶2（ALDH2）基因多态性与饮酒因素交互作用在广西原发性肝癌发生中的作用。方法 对广西壮族自治区300例肝癌患者和292例正常对照人群进行流行病学调查研究，并用PCR-RFLP方法检测ALDH2基因型。结果 肝癌组和对照组中ALDH2变异基因型携带者分别占50．33％和47．95％（P=0．561）。肝癌人群ALDH2基因型不存在区域和民族差异（P〉0．05）。饮酒频度每周≥3次的ALDH₂²携带者发生肝癌的危险性是饮酒频度每周〈3次的ALDH2＊1携带者的3、34倍（95％CI1．75～6．41）。HBsAg阳性者发生肝癌的危险性明显高于HbsAg阴性者（P〈0．001）。结论 ALDH2基因型不构成壮汉族间肝癌发病差异的基础，频繁饮酒可能是ALDH2基因变异基因型携带者发生肝癌的危险因素。     

醇醛脱氢酶基因多态和饮酒习惯与肝癌易感性

目的研究乙醇脱氢酶2（ADH2）和乙醛脱氢酶2（ALDH2）基因多态及饮酒习惯与肝癌的易感性。方法对208例原发性肝癌和208例对照调查饮酒习惯,采用RCT-RFLR方法检测ADH2和ALDH2基因型。结果1）病例与对照ADH2和ALDH2基因型分布频率差异均无统计学意义。2）携带AL-DH2^1＊2或ALDH2^2＊2基因型且饮酒总量〉3kg年者,发生肝癌危险性是携带AL-DH211基因型不饮酒者的3.30倍（95%CI=1.24～8.83）;而携带ADH2^1＊2或ADH2^2＊2基因型者且饮酒总量〉3kg年与携带ADH211基因型不饮酒者相比,患肝癌危险性无显著增加。3）携带AL-DH2^1＊2或ALDH2^2＊2同时携带ADH2^1＊2或ADH2^2＊2基因型且饮酒总量〉3kg年者,与携带ALDH2^1＊1同时携带ADH2^1＊1基因型且饮酒总量≤3kg年者相比,患肝癌OR值虽有增加但未达显著性（OR=4.26,95%CI=0.63～29.08）。4）HBsAg阳性并携带ALDH2^1＊2或ALDH2^2＊2基因型且饮酒〉3kg年者,与HBsAg阴性并携带ALDH2^1＊1基因型且饮酒≤3kg年者相比,患肝癌危险升高49.71倍（95%CI=5.51～448.96）。结论大量饮酒和肝癌的关联与ALDH2基因有关,而与ADH2基因无关。     

乙醇脱氢酶2基因多态和饮酒习惯与肝癌易感性

目的:研究乙醇脱氢酶2(ADH2)基因多 态性和饮酒习惯与肝癌的易感性关系。方法:在 肝癌高发区江苏省泰兴市采用病例对照研究方 法,病例为确诊的原发性肝癌(207例)新发病例, 对照(207例)按1∶1配对,选取与病例同性别、年 龄相差不超过2岁,与病例居住同村或同一街道 的非肿瘤居民,调查研究对象的饮酒习惯等因素, 并采用聚合酶链反应 限制性片段长度多态性 (PCR PFLP)方法检测了他们的ADH2基因型。 结果:1)病例组及对照组中ADH2 1/ 1、 ADH2 1/ 2、ADH2 2/ 2的基因型分布频 度分别为10.14%、63.77%、26.09%及12.56%、 46.86%、40.58%。与携带ADH2 1/ 1基因型 者相比,无论是携带ADH2 2/ 2(OR=0.8, 95%CI=0.39～1.64)或ADH2 1/ 2(OR= 1.68,95%CI=0.86～3.32)基因型者,患肝癌的危 险性均无明显增加。2)携带ADH2 1/ 2或 ADH2 2/ 2基因型饮酒者与携带ADH2 1/ 1基因型的不饮者相比,患肝癌的风险差异 无统计学意义(OR=0.997,95%CI=0.296～ 3.354)。3)在调整了年龄、性别、HBsAg、肝硬化和 血吸虫病因素后,结合饮酒习惯将前者与后者相 比,若开始饮酒年龄<25岁、饮酒量>3kg/月、饮 酒年数>23年和饮酒总量(千克年)>3时,前者 患肝癌的危险性分别是后者的1.88(95%CI=0.53 ～6.70)、1.35(95%CI     

CYP2E1基因多态性与肝癌易感性的关系

目的 :研究细胞色素P45 0 2E1(CYP2E1)基因多态性与肝癌易感性的关系。方法 :在肝癌高发区泰兴市进行病例对照研究 ,调查研究对象的饮酒习惯 ,以PCR RFLP方法分析CYP2E1基因型。结果 :肝癌病例组与对照组中CYP2E1变异基因型 (C1/C2 C2 /C2 )的分布频率分别为 41 0 6%和 3 7 0 2 % ,两者差异无统计学意义 ;从饮酒习惯等方面分析 ,携带CYP2E1变异基因型的饮酒者与携带野生基因型的不饮酒者间患肝癌危险性差异无统计学意义。结论 :CYP2E1基因多态性与泰兴市肝癌的发生无关     

乙醛脱氢酶2基因多态性和饮酒习惯与肝癌发生的关系研究

目的 :研究当地饮酒习惯与乙醛脱氢酶 2 (ALDH2 )基因的多态性对肝癌危险性的影响。方法 :在江苏泰兴市选择 1999年 9月 1日～ 2 0 0 0年 12月 31日新发肝癌病人 88例 ,按性别、年龄和居住地1∶1配对 ,进行流行病学调查研究 ,并应用PCR RFLP方法检测研究对象的ALDH2基因型。统计分析采用EpiInfo软件包。结果 :饮大量高度酒能显著增加ALDH2变异基因型携带者患肝癌的危险性 (OR=7 2 0 ,χ2 =6 6 5 ,P <0 0 1)。结论 :ALDH2基因多态性和饮酒习惯与肝癌的发生有关。     

饮酒及酒精代谢酶基因多态与食管癌发病风险

[目的]研究饮酒及乙醇脱氢酶2（ADH2）和乙醛脱氢酶2（ALDH2）基因多态性与食管癌发病风险关系。[方法]对江苏省泰兴市221食管癌新发病例和191对照调查饮酒习惯等因素,采用聚合酶链反应（PCR）和变性高效液相色谱法（DHPLC）检测研究对象ADH2和ALDH2基因型。[结果]①携带ALDH2 G/A或A/A饮酒者患食管癌危险性,分别是携带ALDH2G/G饮酒者或不饮酒者的3.08倍和3.05倍（OR=3.08,95%CI：1.65～5.78;OR=3.05,95%CI：1.49～6.25）。②携带ALDH2 G/A或A/A且酒精消耗总量≥2.5kg·年者患食管癌风险是携带ALDH2G/G且酒精消耗总量〈2.5kg·年者12.31倍（OR=12.31,95%CI：3.01～50.37）。③携带ALDH2 G/A或A/A者患食管癌风险,随酒精消耗总量增加呈趋势性显著上升（P=0.023）,当达到≥2.5kg·年时患食管癌风险是不饮酒者的6.58倍。④同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G且酒精消耗总量≥2.5kg·年者患食管癌风险,是同时携带ALDH2G/G和ADH2A/A且酒精消耗总量〈2.5kg·年者（OR=35.59,95%CI：1.86～680.1）。[结论]可将酒精消耗总量达≥2.5kg·年作为显著增加携带ALDH2 G/A或A/A饮酒者患食道癌风险的阈值。对同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G且酒精消耗总量≥2.5kg·年者,劝其戒酒和定期随访对降低食管癌危害十分有益。     

CYP2E1基因多态性与肝癌易感性的关系

目的：研究细胞色素P450 2E1(CYP2E1)基因多态性与肝癌易感性的关系。方法：在肝癌高发区泰兴市进行病例对照研究，调查研究对象的饮酒习惯，以PCR RFLP方法分析CYP2E1基因型。结果：肝癌病例组与对照组中CYP2E1变异基因型(C1／C2 C2／C2)的分布频率分别为41．06％和37．02％，两者差异无统计学意义；从饮酒习惯等方面分析，携带CYP2E1变异基因型的饮酒者与携带野生基因型的不饮酒者间患肝癌危险性差异无统计学意义。结论：CYP2E1基因多态性与泰兴市肝癌的发生无关。     

环氧合酶-2抑制剂Celebrex对胰腺癌PC-3细胞株VEGF和PGE2表达的影响

目的 探讨选择性环氧合酶(COX)—2抑制剂Celebrex，对胰腺癌PC—3细胞株血管内皮生长因子(VEGF)和前列腺素E2(PGE2)表达的影响。方法 应用酶联免疫吸附测定(ELISA)和放射免疫测定(RIA)方法，检测选择性COX—2抑制剂Cdebrex与胰腺癌PC—3细胞VEGF和PGE2表达间的时间一效应关系和剂量—效应关系。结果 Celebrex在一定时间和剂量范围内可抑制PC一3细胞株中VEGF和PGE2的表达，且VEGF和PGE2的变化趋势一致。结论 COX一2可能参与了PC一3细胞VEGF的分泌，而PGE2则可能在该过程中起着重要的介导作用。     

THE INFECTION OF EBV FOR CERVICAL EPITHELIUM-A NEW CAUSITIVE AGENT IN THE DEVELOPMENT OF CERVICAL CARCINOMAS?

Epstein-Barr virus was considered as a caustive agent for Burrkitt' s lymphoma and non-malignant B lymphocytes proliferation. The recent studies revealed the striking association of the Infection of EBV with the development of human epithelial tumors. 43 specimens of normal exfoliated cervical epithelial cells, 47 biopsies of chronic cervlcitis and 80 tissue samples of cervical carcinomas were tested for the presences of EBV W fragments by using dot blot hybridization method. The results showed that the detectable rates of EBV DNA sequences In the normal exfoliated epithelium, the chronic cervlcitis and cervical carcinomas were 44.16%, 12.77% and 13.75%, respectively. Eleven EBV positive DNA samples from cervical cancers were also examined for the presence of HPV DNA. The result showed 9 out of 11 were HPV DNA positive, the cultanious infectious rate of both viruses was about 81.81%.In this paper, the EBV genomes existed In the part of biopsies of cervical carcinomas were first reported. The results Imp     

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

BackgroundThe toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC).MethodsCell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules.ResultsMD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing.ConclusionsOur findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.     

In vitro phosphorylation of BRCA2 by the checkpoint kinase CHEK2

Germline mutations in both BRCA2 and CHEK2 are associated with an increased risk for male breast cancer. To search for potential interactions between the products of these breast cancer susceptibility genes, we undertook systematic mapping of BRCA2 for potential phosphorylation sites by CHEK2. In vitro kinase assays and mass spectrometric analysis identified a 50 amino-acid fragment within the N-terminus of BRCA2 potentially targeted by CHEK2, containing two major phosphopeptides. Inducible overexpression of this peptide, but not a derivative with mutated phosphorylation sites, leads to increased chromosome fragmentation and suppression of cellular proliferation. These results suggest a link between CHEK2 and BRCA2 pathways, which may contribute to the spectrum of cancers associated with germline CHEK2 mutations.     

COX-2与子宫内膜癌的关系

目的 研究子宫内膜癌中环氧合酶-2（cyclooxygenase-2，COX-2）的表达及其与临床病理因素的关系。探讨COX-2在子宫内膜癌发生、发展中的作用。方法 采用免疫组织化学S-P法检测20例正常子宫内膜、20例不典型增生子宫内膜、45例子宫内膜癌等3组标本的COX-2蛋白表达水平。结果 正常子宫内膜、不典型增生内膜及子宫内膜癌组织中率分别为15.0％（3／20）、50.0％（10／20）、77．8％（35／45），由正常子宫内膜至子宫内膜癌的进展过程中，COX-2的阳性表达率呈现逐渐增高的趋势。COX-2阳性表达率与子宫内膜癌的分期、淋巴结转移、肌层浸润深度、病理类型无明显相关性。高分化内膜癌COX-2阳性表达率（89.3％）高于中低分化内膜癌（58．8％），P〈0．05。结论 COX-2在子宫内膜癌发生、发展中起着重要的作用。COX-2表达上调可能是子宫内膜癌形成中的早期事件。     

VEGF、MMP-2与TIMP-2在大肠癌中的表达

 目的　研究VEGF、MMP 2与TIMP 2在大肠癌组织中的表达、相互关系及与肿瘤生物学行为的相关性。方法　对 5 4例大肠癌患者的手术切除之癌组织和癌周正常组织 ,应用免疫组织化学方法检测其VEGF、基质金属蛋白酶MMP 2和组织金属蛋白酶抑制剂TIMP 2的表达情况 ,探讨两者之间的相互关系及其与肿瘤生物学行为的相关性。结果　VEGF、MMP 2与TIMP 2这三种蛋白在肿瘤组织中表达水平明显高于在正常组织中的表达。这三种蛋白的表达呈正相关 ,且表达水平与组织类型、组织分化程度、淋巴结转移、临床分期和五年生存率有统计学相关性 (P <0 .0 5 )。结论　大肠癌中VEGF、MMP 2与TIMP 2的表达 ,可能是癌肿发生、生长和浸润转移的重要因素 ,可作为判断肿瘤恶性程度的重要指标。     

PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling

The aim of this study was to investigate the underlying mechanisms that transforming growth factor- (TGF- )-mediated epithelial-to-mesenchymal transition (EMT) in tumor cells contributes to 5-FU resistance. A series of experiments involving cell viability and caspase activity analyses, siRNA transfection, RNA isolation, and quantitative-PCR (qPCR) assay, cell migration analysis, Western blotting analysis of total protein and membrane protein were performed in this study. Mouse xenograft model was used to determine the effect of the PAR2 inhibitor in vivo. In this study, we found that protease-activated receptor 2 (PAR2) induction in 5-FU therapy is correlated with TGF- -mediated EMT and apoptosis resistance. PAR2 and TGF- were both activated in response to 5-FU treatment in vivo and in vitro, and whereas TGF- inhibition sensitized CRC cells to 5-FU and suppressed cell migration, PAR2 activation eliminated the effect of TGF- inhibition. Conversely, siRNA-mediated PAR2 depletion or PAR2 inhibition with a specific inhibitor produced a similar phenotype as TGF- signal inhibition: 5-FU sensitization and cell migration suppression. Moreover, the results of xenograft experiments indicated that the PAR2 inhibitor can enhance cell killing by 5-FU in vivo and suppress EMT signaling. Our results reveal that the TGF- effects require the coordinating action of PAR2, suggesting that PAR2 inhibition could be a new therapeutic strategy to combat 5-FU resistance in CRC.     

HER-2基因和基质金属蛋白酶-9在大肠癌中的表达和临床意义

目的探讨HER-2和基质金属蛋白酶-9在大肠癌中的表达及其临床意义。方法采用Elivision免疫组化检测法，用HER-2抗体、MMP-9抗体标记50例大肠癌组织标本。综合考虑切片中阳性细胞占所观察同类细胞的百分比和阳性细胞着色强度来判断。结果MMP-9、HER-2表达与大肠癌患者性别、年龄、肿瘤部位无相关性，（P〉0．05）。DukesC期、DukesD期患者中MMP-9、HER-2阳性表达率明显高于DukesA期、DukesB期，（P〈0．05）。大肠癌A型血患者中MMP-9、HER-2阳性率明显高于非A型血患者，（P〈0．05）。但HER-2与MMP-9表达间无协同作用。结论MMP-9、HER-2的表达均是反映大肠癌侵袭、转移的重要标记物，它们独自影响和调节大肠癌侵袭和转移。     

基质金属蛋白酶-2单核苷酸多态性与非小细胞肺癌的关系

目的:研究基质金属蛋白酶-2(MMP-2)单核苷酸多态性与非小细胞肺癌(NSCLC)的关系。方法:以聚合酶链反应和DNA测序等基因多态性分析方法,分别检测非小细胞肺癌患者和正常对照MMP-2-1306T/C基因型,比较不同基因型与肺癌的关系。结果:与MMP-2-1306TT或MMP-2-1306CT基因型携带者比较,MMP-2-1306CC基因型携带者的非小细胞肺癌易感性较高。结论:MMP-2基因的多态性可能与非小细胞肺癌的遗传易感性有关。     

MMP-2、TIMP-2和Cathepsin D表达与结肠癌侵袭转移的关系研究

目的探讨MMP-2、TIMP-2和Cathepsin D在结肠癌侵袭转移中的作用。方法采用组织芯片技术,应用免疫组化方法,检测77例结肠癌原发灶及其淋巴结转移灶组织中MMP-2、TIMP-2和Cathepsin D的表达情况。结果MMP-2、TIMP-2和Cathepsin D的高表达率在原发灶和转移灶中分别为20.78%VS41.56%、61.04%VS44.16%、75.32%VS53.25%。MMP-2高表达率在原发灶显著低于转移灶;TIMP-2和Cathepsin D高表达率在原发灶均显著高于转移灶（P均〈0.05）。MMP-2表达强度在原发灶显著低于转移灶,TIMP-2及Cathepsin D表达强度在原发灶显著高于转移灶（P〈0.001）。结论MMP-2、TIMP-2和Cathepsin D的表达与结肠癌细胞浸润和转移能力有关,高表达MMP-2和低表达TIMP-2的癌细胞更易发生淋巴道转移。