幽门螺杆菌感染和白细胞介素1基因多态性与胃癌易感性关系的研究进展

胃癌是危害人类生命健康的主要恶性肿瘤之一^[1]，病死率高，对人类健康和生命造成严重威胁，在世界不同国家或同一国家不同地区其发病及死亡水平存在很大差别。胃癌的病因和危险因素很复杂，是环境因素和遗传因素综合作用的结果，流行病学研究认为，胃癌的发生是多因素、多阶段的过程。     

Cyclin D1在胃癌中的表达及其与HP感染的关系

ＣｙｃｌｉｎＤ１是近年提出的重要原癌基因［１］，其异常改变如重排、扩增和过度表达存在于多种肿瘤细胞中。目前，对其在胃癌中的研究报道甚少，我们采用免疫组化方法探讨了ＣｙｃｌｉｎＤ１在胃癌中的表达状况及其与幽门螺杆菌（ＨＰ）感染的关系。现报告如下。１资料...     

IL-1基因多态性与Hp感染后胃癌易感性的研究

目的 研究白细胞介素1B基因（IL-1B）启动子区域-31位点和-511位点及白细胞介素1受体拮抗剂基因（IL-1RN）多态性在我国北方人群胃癌患者与胃炎患者中的分布，探讨各基因型与胃癌的相关性。方法 收集126例胃癌患者与125例慢性胃炎患者（对照组）的外周血标本和流行病学资料，提取基因组DNA；IL-1RN基因采用PCR方法直接测定，IL-1B-31基因采用PCR-CTPP方法，IL-1B-511基因采用PCR-RFLP的方法进行基因分型。通过快速尿素酶、^14C呼气试验及Hp血清IgG抗体的方法检测Hp感染。结果 IL-1RN有5种基因型，分别为1／1、1／3、1／4、1／2和2／2型，其出现频率在胃癌组中分别为76．19％、4．76％、6．35％、11．90％和0．79％；在对照组分别为76．00％、4．00％、4．80％、13．60％和1．60％。各基因型在胃癌组和对照组中分布差异无统计学意义。IL-1B-31位点有3种基因型C／C、C／T和T／T型，在胃癌组中的频率分别为12．70％、47．62％和39．68％；在对照组中的频率分别为28．00％、48．80％和23．20％。与C／C型相比较，携带T／T基因型者胃癌发生的风险增加，OR=3．772（95％CI=1．786-7．966）。IL-1B-511位点有3种基因型C／C、C／T和T／T型，在胃癌组中的频率分别为19．20％、56．80％和24．00％；在对照组中的频率分别为23．38％、49．19％和27．42％。各基因型在胃癌组和对照组中分布差异无统计学意义。结论 IL-1B基因启动子区域-31位点的基因多态性可能与国人胃癌易感性相关；尚未有证据表明IL-1RN和IL-1B-511位点的基因多态性与国人胃癌易感性相关。     

细胞周期素D1在大肠癌中的表达及意义

目的：探讨细胞周期素D1（CD1）与大肠癌的发生、进展及预后的关系。方法：收集24例手术切除的大肠癌标本,同时取距癌灶5cm以外的癌旁组织及10cm以外的正常组织,用原位杂交的方法检测癌组织、癌旁组织及正常组织中CD1mRNA的表达,同时结合临床病理资料进行分析。结果：24例大肠癌组织中CD1mRNA阳性9例,阳性率37．5％;癌旁组织仅有1例阳性,阳性率4．2％;正常组织未见阳性表达。癌旁组织和正常组织均与癌组织有显著性差异（P＜0．01）。CD1mRNA的表达在浸润至浆膜层组明显高于浸润至肌层组（P＜0．05）;有淋巴结转移组及晚期病变（Dukes B C D期）组亦明显高于无淋巴结转移及早期病变（Dukes A期）组（P＜0．05）。CD1mRNA的表达高低与年龄、性别、癌灶直径大小、分化程度及是否有远处转移无明显关系（P＞0．05）。结论：CD1mRNA过度表达与大肠癌的发生、发展及转移有关。     

幽门螺杆菌感染宿主炎性因子基因多态性与胃癌的关系

幽门螺杆菌(Hp)感染被认为是胃癌发生发展的重要危险因素,而基因多态性可能是Hp感染导致不同结局的内在因素,此文综述了与Hp感染诱导的胃癌发病有关的宿主炎性因子的基因多态性。     

白细胞介素-1B-511单核苷酸多态性与胃癌关系的流行病学研究

目的研究中国胃癌高、低发区白细胞介素（IL）-1B-511单核苷酸多态性、幽门螺杆菌（Hp）感染与胃癌的芙系。方法胃癌高发区（陕西省）胃癌患者、健康志愿者各102例，胃癌低发区（广东省）胃癌患者、健康志愿者各104例，两组人群在性别比及年龄上均匹配。采用限制性片段长度多态性（PCR—RFLP）分析IL-1B-511单核苷酸多态性，酶联免疫吸附法（ELISA）检测血清抗Hp—IgG抗体。结果在胃癌低发区，胃癌患者IL-1B-511T／T基因型频率明显高于对照人群（26．9％比13．4％，X^2=5．85，P〈0．05；OR=2．37，95％CI为1．16～4．82）。在胃癌高发区，胃癌患者IL-1B-511 T／T基因型频率与对照人群尢明显差异（27．5％比24．5％，X^2=0．41，P〉0．05）；高发区对照人群的IL-1B-511 T／T基因型频牢明显高于低发区相应人群（24．5％比13．4％，X^2=4．1，P〈0．05）。Hp感染轻度增加低发区人群发生胃癌的危险性（OR=3．03，95％CI为1．61～5．71），而IL-1B-511 T／T基因型增加Hp感染后胃癌发生的危险性（OR=8．0，95％CI为1．39～35．7）。结论IL-1B-511 T／T基因型与中国人胃癌发生有关，IL-1B-511 T／T基因型增加HP感染后胃癌发生的危险性。     

胃癌白细胞介素-1β基因多态性与胃癌关系的荟萃分析

背景:随着胃癌病因研究的深入,目前发现许多宿主因素与胃癌的形成密切相关,白细胞介素(IL)-1β基因多态性成为重要的候选因素.目的:综合评价IL-1β-511等位基因及其基因型在胃癌发生中的作用,以期较深入地揭示IL-1β基因多态性与胃癌的关系.方法:共有7篇发表于1994年1月～2003年10月期间的有关IL-1β基因多态性与胃癌关系的国内外病例对照研究纳入荟萃分析,采用Review Manager 4.2统计软件对其结果进行定量综合分析.结果:以IL-1β-511位点的C/C基因型为对照,C/T、T/T和*/T基因型均为胃癌的危险因素,其OR值(95%CI)分别为1.78(1.51.2.10)、1.92(1.07～3.44)和1.79(1.54～2.07),但T/T基因型经敏感性分析后结果逆转.结论:IL-1β-511位点的C/T和*/T基因型是胃癌的危险因素,但T/T基因型与胃癌的关系尚未明确.     

细胞周期素D1及P16蛋白表达与肺癌临床病理特征的关系

目的　研究细胞周期素D1(CyclinD1)及P16蛋白在肺癌中的表达及其与肺癌临床病理特征的关系。方法　应用免疫组化SP法对 5 9例肺癌组织及 47例癌旁肺组织中CyclinD1及P16蛋白进行检测。结果　CyclinD1在肺癌组织中阳性表达率为 61.0 % (3 6/ 5 9) ,显著高于癌旁肺组织 (17.0 % ,8/ 47) ,P <0 .0 1;而P16蛋白在肺癌中阳性表达率 (4 0 .7% ,2 4/ 5 9)低于癌旁肺组织 (76.6% ,3 6/ 47) ,P <0 .0 1。肺癌组织CyclinD1及P16蛋白表达与患者年龄、性别、肿瘤组织学类型、分期及淋巴结转移等均无明显相关 (P >0 .0 5 ) ,与肿瘤分化程度有显著相关性 ,肺癌中CyclinD1与P16蛋白表达呈显著负相关 (r =-0 .763 ,P <0 .0 1)。结论　CyclinD1过表达及P16表达缺失与肺癌的发生密切相关。CyclinD1和P16蛋白异常表达可能是肺癌发生过程中的早期事件 ,可作为判断肺癌分化程度的参考指标 ,具有早期诊断价值     

hTERT基因多态性与胃癌易感性的研究

人端粒酶逆转录酶(hTERT)作为端粒酶的关键酶参与了包括胃癌在内的多种肿瘤的发生和发展,有研究发现该基因的多个单核苷酸多态性(SNP)位点与多种恶性肿瘤具有不同程度的相关性。目的:探讨hTERT基因rs2853676和rs2853677位点SNP与胃癌遗传易感性的关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法检测297例胃癌、105例萎缩性胃炎和402例对照组患者rs2853676和rs2853677位点的基因多态性,采用病理学检查和~(13)C-尿素呼气试验检测幽门螺杆菌(Hp)感染。结果:胃癌组rs2853676位点AA基因型频率显著高于对照组(15.2%对6.5%,P=0.01),AA基因型携带者患胃癌的风险增加2.47倍(95%CI:1.46~4.16)。三组rs2853677位点CC、TC、TT基因型频率差异无统计学意义。与对照组相比,萎缩性胃炎组和胃癌组Hp感染率显著升高(64.8%、56.9%对40.3%,P均0.01),OR值分别为2.73(95%CI:1.74~4.26)、1.96(95%CI:1.44~2.67)。Logistic回归分析发现,Hp感染与基因突变无明显交互作用。结论:hTERT基因rs2853676基因多态性与胃癌遗传易感性有关,其增加胃癌的风险与Hp感染可能无关。     

IL-1B基因多态性与幽门螺旋杆菌感染后胃癌发病的关系

取35例胃癌(胃癌组)及37例慢性胃炎(对照组)患者全血标本,使用基因芯片检测技术,结合PCR 体外扩增方法,检测人IL1B-31和-511位点基因多态性,并用13C尿素呼气试验、免疫印迹试验检测Hp感染情况.结果胃癌组Hp感染率高于对照组(P＜0.05),胃癌组IL-1B-31位点T携带子的频率高于对照组(P＜0.05).与C/C型比较,T携带子基因型者发生胃癌的风险增加,OR=4.237(95%CI:1.563～10.000);IL-1B-511位点的各基因型频率在两组间差异无统计学意义(P＞0.05).认为IL-1B-31位点基因多态性可能增加Hp感染后中国人发生胃癌的危险性.     

GG genotype of cyclin D1 G870A polymorphism is associated with non-cardiac gastric cancer in a high-risk region of China

Objective. Cyclin D1 (CCND1) is a regulatory protein involved in the cell cycle of both normal and neoplastic cells. Polymorphism of this gene at codon 242 in exon 4 (A870G) has an impact on the risk of several human cancers. The purpose of this study was to study the relation between the CCND1 A870G gene polymorphism and the risk of non-cardiac gastric cancer in a Chinese population. Material and methods. The study population consisted of 159 patients with non-cardiac gastric cancer and 162 cancer-free controls. CCND1 870A/G polymorphism was genotyped by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and sequencing. Results. CCND1 genotype distribution among the patients was significantly different from that among controls; AA (odds ratio (OR)=0.348, 95% CI: 0.163–0.742) and GA (OR=0.715, 95% CI: 0.506–1.012) genotypes were significantly lower in the gastric cancer patients than in the controls when subjects with the GG genotype served as the reference category. In other words, the risk of gastric cancer for subjects with the GG genotype was 2.8 times that of subjects with the AA genotype, and 1.4 times that of subjects with the GA genotype. Furthermore, in the stratification analyses, the risk of GG genotype was more evident in subjects ≥60 years of age and those positive for Helicobacter pylori (H. pylori) infection. Conclusions. The CCND1870 GG genotype is associated with an increased risk for non-cardiac gastric cancer in patients in a high-risk area of China. Larger studies with multiple polymorphisms are needed to verify this finding and the function of this polymorphism needs to be further investigated.     

Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population

Purpose: To investigate whether the common cyclin D1 (CCND1) A870G polymorphism is a risk factor for colorectal cancer (CRC) in an Indian population. Methods: In this study, 301 newly diagnosed CRC patients and 291 healthy control subjects were genotyped by the PCR-RFLP method. Genotype frequencies were compared between cases and controls, and the association of genotypes with CRC was studied. Results: The CCND1 870 A allele was more frequently observed in CRC patients than controls (0.63 vs. 0.56, P=0.01), and after adjustment for age, sex, smoking habits, family history, family income and the consumption of meat, fish, vegetables and fruit, an increased risk was observed for the AA genotype compared to the GG+AG genotype (OR=1.56; 95% CI: 1.10–2.21). The increased risk were also found for colon (OR=1.96; 95% CI: 1.08–3.57) and rectal cancer (OR=1.51; 95% CI: 1.04–2.19). No correlation was observed between genotypes and age of diagnosis of CRC (49.9, 48.7 and 49.4 years for the GG, AG and AA genotypes, respectively; P=0.84). Multivariate analysis also revealed a stronger positive association with the AA genotype among patients with high meat intake (OR=2.67; 95% CI: 1.29–5.51), and particularly significant inverse associations with the GG+AG genotypes were also found for those with high vegetable consumption (OR=0.46; 95% CI: 0.27–0.79 of 2–3 servings/day, and OR=0.31; 95% CI: 0.18–0.53 for >3 servings/day) and fish intake (OR=0.48; 95% CI: 0.28–0.82). Conclusion: These data support the hypothesis that the CCND1 A870G polymorphism may increase the risk of CRC in our Indian population.     

老年人胃癌与谷胱甘肽转硫酶P1基因多态性关系的研究

目的 探讨幽门螺杆菌(Hp)感染及谷胱甘肽转硫酶P1(GSTP1)基因多态性与胃癌的关系.方法 选择老年胃癌患者(胃癌组)98例和胃镜检查正常者(对照组)149例,以快速尿素酶试验、13C-尿素呼气试验或活检标本吉姆萨染色(Giemsa)检测Hp感染;通过聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法检测GSTP1基因型.结果 Hp感染率胃癌组(54.1%)与对照组(40.9%)比较,差异有统计学意义(x2=4.11,P＜0.05);具有GSTP1突变纯和基因型并有Hp感染阳性的人群胃癌发病风险显著增加OR值5.44(1.26～26.79)(x2=7.13,P＜0.01).结论 老年患者Hp感染和GSTP1基因型多态性与胃癌的发病风险有关.

Abstract：

Objective To study the relationships of Helicobacter pylori (Hp) infection and genetic polymorphisms of glutathione s-transferase P1 (GSTP1) with gastric cancer (GC). Methods The 98 patients with GC and 149 controls with normal finding at endoscopy were enrolled for this study. The rapid urease test (RUT), 13C- urea breath test (13C-UBT) and Giemsa staining of biopsy samples were used to check Hp infection. PCR-based restriction fragment length polymorphisms (PCR-RFLP) was used to detect GSTP1 genotype. Results The rate of Hp infection was higher in GC group than in control group (54.1% vs. 40.9%, x2 =4.11, P＜0. 05). The risk of GC would significantly increase in the GSTP1 homozygous mutant gene (MM) group with Hp infection (OR=5.44, 95%CI 1. 26-26. 79, x2=7.13, P＜0.05). Conclusions Hp infection and GSTP1 genetic polymorphisms are associated with gastric cancer risk in the elderly.     

幽门螺杆菌vac A基因型与胃癌及癌前病变的相关性

目的　分析胃癌高发的西安地区幽门螺杆菌 (Hp)分离株空泡形成毒素基因 (vacA)的基因型与胃癌及癌前病变的相关性。方法　建立Hp菌株库并采用聚合酶链反应 (PCR)技术进行vacA基因s、m分型。结果　 192株菌株中 ,s1型 174株 ,占 90 6 % ;s2型 18株 ,占 9 4%。m1型 99株(5 1 6 % ) ;m2型 93株 (4 8 4% )。所有菌株的PCR产物均为s1或s2 ,m1或m2。s1在胃癌分离株中表达占 94 5 % ,其中s1a型明显多于s1b(P <0 0 5 ) ;但m1和m2表达差异不显著。在胃炎组 ,仍是s1型表达占多数 (89 8% ) ,但s1a和s1b、m1和m2表达的差异无显著性。结论　无论胃癌还是胃炎均以s1型为主 ,且在胃癌组s1a型表达显著高于s1b型 ,它是否是促进胃黏膜恶性变的指标 ,尚需进一步研究。但可肯定西安地区vacA基因型以致病性较强的产毒型为主。     

幽门螺杆菌感染者胃粘膜癌前病变与Fas抗原表达的关系

目的研究幽门螺杆菌(Hp)感染后胃粘膜癌前病变中 Fas 抗原表达的情况,了解 Hp 在胃癌发生过程中的作用。方法采用免疫组织化学等方法检测83例经病理证实为慢性胃炎病人胃粘膜上皮细胞中 Fas 抗原的表达情况。结果在浅表性胃炎、萎缩性胃炎、肠化生及异型增生中,Fas 抗原表达率分别为20.00%、36.36%、73.33%、43.75%,Fas 抗原在肠化生中的表达率显著高于浅表性胃炎、萎缩性胃炎及异型增生(P<0.01及P<0.05)。Hp 感染者 Fas 抗原表达率为60.71%,显著高于 Hp 阴性者的22.22%(P<0.01)。在萎缩、肠化生及异型增生等癌前病变中,Hp 感染者与未感染者表达率分别为65.96%及28.57%(P<0.01)。结论 Hp 感染对 Fas 抗原表达有一定的影响,Hp 感染可促进 Fas 抗原表达增加,这可能是 Hp 感染诱导胃粘膜上皮细胞凋亡的机制之一。     

特异性核酶对肝星状细胞细胞周期蛋白D1基因表达及激活的影响

目的研究抗细胞周期蛋白D1核酶对大鼠肝星状细胞(HSC)细胞周期蛋白D1基因表达及激活的影响。方法构建抗细胞周期蛋白D1核酶的真核表达载体,将其转染入HSC-T6细胞,同时以空白及转染pLXSN作为对照,用G418筛选出阳性细胞克隆;分别用RT-PCR和Western印迹法检测细胞周期蛋白D1和α-平滑肌肌动蛋白(α-SMA)的表达。结果转染核酶832的HSC细胞周期蛋白D1 mRNA和蛋白表达均受到明显抑制,分别为对照组的42．22％(P<0．01)和58．29％(P<0．01),同时α-SMA mRNA和蛋白表达与对照组相比也显著下降(P值均<0．01)。结论载体表达的特异性核酶能有效地抑制HSC的细胞周期蛋白D1的表达和激活。     

No relationship between IL-1B gene polymorphism and gastric acid secretion in younger healthy volunteers

AIM: To investigate the influence of IL-1B-511 gene polymorphism on IL-1B mRNA expression and gastric acid output in individual with or without Helicobacter pylori (H pylori) infection. METHODS: IL-1B mRNA expression and gastric acid secretion in 117 health volunteers were assayed using semi-quantitative RT-PCR and gastric juice assay, respectively. Pepsinogen (PG) Ⅰ and Ⅱ of 255 subjects (including 117 health volunteers) were also examined. RESULTS: T/T genotype individuals with H pylori infection had a more decreased PG Ⅰ/Ⅱ ratio. In gastric antrum mucosa, the individuals with H pylori infection had higher IL-1B expression than those without H pylori infection, but there was no obvious difference among each genotype. In gastric corpus, the individuals with H pylori infection had a significantly higher IL-1B expression than those without H pylori infection. IL-1B-511T/T genotype was markedly higher as compared with the other two genotypes. Both maximal acid output and basic acid output were similar among each genotype in IL-1B-511 gene locus, regardless of H pylori infection. CONCLUSION: IL-1B-511 T allele does not decrease gastric acid output, although it has a stimulated influence on IL-1B expression. Consequently, the pathway, through which IL-1B plays a central role in gastric cancer development, might not depend on low acid, but on the other regulation mechanisms.     

胃癌及癌前病变中HP感染与p16、CyclinD1表达的关系

目的：探讨胃癌发生、发展过程中幽门螺杆菌（HP）与p16、CyclinD1基因表达的关系。方法：免疫组化S－P法检测p16、CyclinD1。结果：在癌前病变中,HP阳性组的P16阳性表达率低于HP阴性组（P＜0．01）CyclinD1阳性表达率高于HP阴性组（P＜0．01）;在胃癌中HP阳性组的PH阳性表达率与胃癌的浸润,分化程度有关,且低于HP阴性组（P＜0．05）。CyclinD1阳性表达率在HP阳性和表性组间无差异（＞0．05）。结论：在胃癌前病变阶段,HP可能诱导癌基因PH失活和原癌基因CyclinD1激活,影响了p16和CyclinD1的表达,在胃癌中,HP感染对PH表达缺失仍起着重要作用,但不影响CyclinD1的表达。     

白细胞介素-1β介导幽门螺杆菌相关胃癌发生的实验研究

目的 探讨白细胞介素(IL)-1β在幽门螺杆菌(Hp)相关胃癌发生中可能的作用机制.方法 以人胃永生化上皮细胞株(GES-1)和胃癌细胞株(AGS)为研究对象,采用四甲基偶氮唑盐比色法测定IL-1β对细胞增殖的影响,流式细胞术碘化丙啶单染法测定IL-1β对Hp(NCTC 11637)诱导细胞凋亡的影响.分别应用RT-PCR法和流式细胞术(荧光定量法)检测IL-1β对细胞环氧合酶-2(COX-2)mRNA和蛋白表达的影响.以兔离体壁细胞为研究对象,应用14C-氨基比林(14C-AP)摄取法检测IL-1β对组胺刺激壁细胞酸分泌的影响,应用RT-PCR法分析IL-1β对壁细胞H+-K+-ATP酶α亚基mRNA表达的影响.结果 IL-1β能刺激GES-1和AGS细胞增殖,抑制Hp诱导的GES-1和AGS细胞凋亡.IL-1β能诱导GES-1 COX-2表达,上调AGS细胞COX-2表达;诱导GES-1和AGS细胞COX-2蛋白表达上调(分别由1.016±0.020和1.070±0.034上调至1.485±0.220和1.501±0.182).IL-1β能抑制组胺刺激的离体壁细胞酸分泌,同时伴H+-K+-ATP酶α亚基mRNA表达下调.结论 IL-1β可能通过两条途径在Hp相关胃癌发生中起作用:上调COX-2表达,破坏胃上皮细胞增殖、凋亡平衡和下调H+-K+-ATP酶表达以抑制壁细胞分泌.     

Influence of interleukin polymorphisms on development of gastric cancer and peptic ulcer

Pro-inflammatory cytokines are produced in the gastric mucosa by inflammatory cells activated by chronic Helicobacter pylori (H. pylori) infection. Polymorphisms of these cytokine genes are associated with individual differences in gastric mucosal cytokine mRNA level, which result in differences in gastric mucosal inflammation, acid inhibition and gastroduodenal disease risk in response to H. pylori infection. Although polymorphisms of interleukin (IL)-1B, IL-1RN and TNF-A have been reported to relate well ...