中国汉族人群TGF-β1基因多态性与胃癌发生的相关性研究
摘要
研究背景胃癌是常见的恶性肿瘤,是严重危害人们健康的疾病之一。胃癌的病因学非常复杂,诸多因素参与了胃上皮细胞从原位癌到胃癌的恶变,如幽门螺杆菌和萎缩性胃炎。然而,只有很少一部分幽门螺杆菌感染者和萎缩性胃炎患者进展为胃癌,遗传因素可能在胃癌的发生中起到一定的作用。有研究表明,胃癌患者的家庭成员其胃癌的发生几率较普通人群大约高3倍。因此,能够影响某些基因表达的基因多态性作为遗传因素之一也可能影响到胃癌的发生。既往的许多研究表明这些基因主要包括那些能够影响炎症反应、DNA修复和代谢相关酶的基因。作为一种能够影响细胞周期、细胞分化、细胞外基质形成的细胞因子,转化生长因子β1(transforming growth factor-β1,TGF-β1)基因多态性也可能影响到胃癌的发生。已有研究得出,TGF-β1与胃癌的发生、进展相关的结论,这提示我们TGF-β1基因多态性与胃癌发生可能存在一定的联系。
目的探讨转化生长因子基因单核苷酸多态性位点C-509T和T869C与胃癌发生的关系。
方法提取中国汉族人群中167例胃癌患者及相同地区193例健康献血者外周血基因组DNA,采用PCR方法扩增TGF-β1基因包含C-509T、T869C这两个多态性位点的片段,分别采用限制性片段长度多态性法(RFLP)和扩增阻滞突变系统聚合酶链技术(ARMS-PCR)明确基因型。使用Mann-WhitneyU-test分析病例组和对照组的年龄分布,采用卡方检验分析病例组和对照组的性别、饮酒和吸烟的分布以及两者之间的基因型的分布。应用PHASE1.0软件构建单倍型并分析单倍型频率。校正性别、年龄、饮酒和吸烟等因素后使用非条件logistic回归计算单倍型与胃癌危险度(OR)和95%的可信区间(95%CI)。以非条件Logistic回归校正混杂因素,并进行多态性与胃癌发生风险关联性的统计学分析。
结果在中国汉族人群中TGF-β1基因2个多态性位点C-509T和T869C均具有多态性(分别为C→T,T→C)。突变基因型-509CT,-509TT,+869TC and+869CC是胃癌发生的危险因素(OR=2.54,P=0.001,CI=1.46-4.40;OR=2.09,P=0.016,CI=1.146-3.80;OR=3.46,P＜0.001,CI=1.91-6.29;OR=4.04,P＜0.001,CI=2.09-7.80)。胃癌患者野生单倍型CT(-509C和+869T)频率显著低于健康对照组(P＜0.001),而突变单倍型TC在胃癌患者中的频率显著高于健康对照组(P＜0.001)。多元线性回归分析表明TC单倍型可明显增加胃癌的发生(OR=3.19,95%CI=1.72-5.90)。
结论结果提示转化生长因子-β1基因多态性-509C＞T、+869T＞C可能是中国汉族人群中胃癌发生的危险因素之一,而突变的TC单倍体型是胃癌发生的较强危险因素,其增加胃癌患病风险约3.19倍。
Background Gastric cancer is one of the most common cancer in China, However,its etiopathogenesis is still indefinite.To our knowledge,many factors such as Helicobacter pylori infection and atrophic gastritis are involved in promoting epithelial cell hyperplasia to in situ carcinoma and invasive disorder. Nevertheless,only a minority of Hp infection or the subjects of chronic atrophic gastritis develop the carcinogenesis,which indicates that heredity distinction may have impact on the risk of gastric cancer.In this regard,family members of patients of gastric cancer preferentially possess approximately three-fold increased risk for developing such disease.Given these findings,it is conceivable that genetic factor plays an important role in the development of gastric cancer.Therefore, gene polymorphisms that can affect the level of expression or the function of correlative genes may modify an individual susceptibility to gastric cancer.As an important cytokine that modulate the cell cycle,the involvement of TGF-β1 in carcinogenesis has been extensively studied for many years.Literatures have demonstrated that TGF-β1 gene polymorphisms may alter the risk of various cancers,such as lung,prostate and breast.
Objectives To investigate whether polymorphisms of TGF-β1 gene can modify the risk of gastric cancer,we conduct this hospital-based,case-control study.
Methods One hundred and sixty-seven cases and 193 gender,age-matched healthy controls were enrolled in this case-control study.TGF-β1 polymorphisms C-509T and T+869C were identified by PCR-RFLP and ARMS-PCR protocols, respectively.
Results Significantly different distributions of both genes were demonstrated between the case and control.Variant genotypes -509CT,-509TT,+869TC and +869CC were associated with increased risk of gastric cancer(P=0.001, OR=2.54;P=0.016,OR=2.09;P＜0.001,OR=3.46;P＜0.001,OR=4.04, respectively).With haplotype analysis,wild type CT(-509C and +869T)led to a lower frequency in case than that in control(P＜0.001),while haplotype TC was more frequent in case than in control(P＜0.001).Multiple logistic regression analysis revealed that individuals with haplotype TC had an increased likelihood of developing gastric cancer(OR=3.19,95%CI=1.72-5.90).
Conclusion Our findings imply that -509C＞T and +869T＞C gene polymorphisms in TGF-β1 may be a critical risk factor of genetic susceptibility to gastric cancer in the Chinese population.
目的探讨转化生长因子基因单核苷酸多态性位点C-509T和T869C与胃癌发生的关系。
方法提取中国汉族人群中167例胃癌患者及相同地区193例健康献血者外周血基因组DNA,采用PCR方法扩增TGF-β1基因包含C-509T、T869C这两个多态性位点的片段,分别采用限制性片段长度多态性法(RFLP)和扩增阻滞突变系统聚合酶链技术(ARMS-PCR)明确基因型。使用Mann-WhitneyU-test分析病例组和对照组的年龄分布,采用卡方检验分析病例组和对照组的性别、饮酒和吸烟的分布以及两者之间的基因型的分布。应用PHASE1.0软件构建单倍型并分析单倍型频率。校正性别、年龄、饮酒和吸烟等因素后使用非条件logistic回归计算单倍型与胃癌危险度(OR)和95%的可信区间(95%CI)。以非条件Logistic回归校正混杂因素,并进行多态性与胃癌发生风险关联性的统计学分析。
结果在中国汉族人群中TGF-β1基因2个多态性位点C-509T和T869C均具有多态性(分别为C→T,T→C)。突变基因型-509CT,-509TT,+869TC and+869CC是胃癌发生的危险因素(OR=2.54,P=0.001,CI=1.46-4.40;OR=2.09,P=0.016,CI=1.146-3.80;OR=3.46,P＜0.001,CI=1.91-6.29;OR=4.04,P＜0.001,CI=2.09-7.80)。胃癌患者野生单倍型CT(-509C和+869T)频率显著低于健康对照组(P＜0.001),而突变单倍型TC在胃癌患者中的频率显著高于健康对照组(P＜0.001)。多元线性回归分析表明TC单倍型可明显增加胃癌的发生(OR=3.19,95%CI=1.72-5.90)。
结论结果提示转化生长因子-β1基因多态性-509C＞T、+869T＞C可能是中国汉族人群中胃癌发生的危险因素之一,而突变的TC单倍体型是胃癌发生的较强危险因素,其增加胃癌患病风险约3.19倍。
Background Gastric cancer is one of the most common cancer in China, However,its etiopathogenesis is still indefinite.To our knowledge,many factors such as Helicobacter pylori infection and atrophic gastritis are involved in promoting epithelial cell hyperplasia to in situ carcinoma and invasive disorder. Nevertheless,only a minority of Hp infection or the subjects of chronic atrophic gastritis develop the carcinogenesis,which indicates that heredity distinction may have impact on the risk of gastric cancer.In this regard,family members of patients of gastric cancer preferentially possess approximately three-fold increased risk for developing such disease.Given these findings,it is conceivable that genetic factor plays an important role in the development of gastric cancer.Therefore, gene polymorphisms that can affect the level of expression or the function of correlative genes may modify an individual susceptibility to gastric cancer.As an important cytokine that modulate the cell cycle,the involvement of TGF-β1 in carcinogenesis has been extensively studied for many years.Literatures have demonstrated that TGF-β1 gene polymorphisms may alter the risk of various cancers,such as lung,prostate and breast.
Objectives To investigate whether polymorphisms of TGF-β1 gene can modify the risk of gastric cancer,we conduct this hospital-based,case-control study.
Methods One hundred and sixty-seven cases and 193 gender,age-matched healthy controls were enrolled in this case-control study.TGF-β1 polymorphisms C-509T and T+869C were identified by PCR-RFLP and ARMS-PCR protocols, respectively.
Results Significantly different distributions of both genes were demonstrated between the case and control.Variant genotypes -509CT,-509TT,+869TC and +869CC were associated with increased risk of gastric cancer(P=0.001, OR=2.54;P=0.016,OR=2.09;P＜0.001,OR=3.46;P＜0.001,OR=4.04, respectively).With haplotype analysis,wild type CT(-509C and +869T)led to a lower frequency in case than that in control(P＜0.001),while haplotype TC was more frequent in case than in control(P＜0.001).Multiple logistic regression analysis revealed that individuals with haplotype TC had an increased likelihood of developing gastric cancer(OR=3.19,95%CI=1.72-5.90).
Conclusion Our findings imply that -509C＞T and +869T＞C gene polymorphisms in TGF-β1 may be a critical risk factor of genetic susceptibility to gastric cancer in the Chinese population.
引文
[1]Blobe,G.C.,Schiemann,W.P.,Lodish,H.F.(2000)Role of transforming growth factor beta in human disease.The New England Journal Of Medicine,342,1350.
[2]Boesen,C.C.,Radaev,S.,Motyka,S.A.,Patamawenu,A.,Sun,P.D.(2002)The 1.1A crystal structure of human TGF-beta type Ⅱ receptor ligand binding domain.Structure,10,913.
[3]Florenes VA;Bhattacharya N;Bani MR;Ben-David Y;Kerbel RS;Slingerland JM(1996)TGF-beta mediated G1 arrest in a human melanoma cell line lacking p15INK4B:evidence for cooperation between p21Cip1/WAF1 and p27Kip1.Oncogene,13,2447.
[4]Wolfraim,L.A.,Walz,T.M.,James,Z.,Fernandez,T.,Letterio,J.J.(2004)P21cip 1 and P27kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2responsiveness.Journal Of Immunology(Baltimore,Md:1950),173,3093.
[5]Ziv,E.,Cauley,J.,Morin,P.A.,Saiz,R.,Browner,W.S.(2001)Association between the T29→C polymorphism in the transforming growth factor betal gene and breast cancer among elderly white women:The Study of Osteoporotic Fractures.JAMA:The Journal Of The American Medical Association 285,2859.
[6]Kim,S.S.,Shetty,K.,Katuri,V.,Kitisin,K.,Baek,H.J.,Tang,Y.,et al.(2006)TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer:role of the beta-spectrin,ELF.Biochemical and Biophysical Research Communications,344,1216.
[7]Derynck,R.,Akhurst,R.J.,Balmain,A.(2001)TGF-beta signaling in tumor suppression and cancer progression.Nature 6enetics,29,117.
[8]Derynck,R.,Zhang,Y.E.(2003)Smad-dependent and Smad-independent pathways in TGF-beta family signalling.Nature,425,577.
[9]Pasche,B.(2001)Role of transforming growth factor beta in cancer.Journal Of Cellular Physiology,186,153.
[10]Grainger DJ;Heathcote K;Chiano M;Snieder H;Kemp PR;Metcalfe JC;Carter ND;Specter TD.(1999)Genetic control of the circulating concentration of transforming growth factor type betal.Human Molecular Genetics 8,93.
[11]Kang,H.G.,Chae,M.H.,Park,J.M.,Kim,E.J.,Park,J.H.,Kam,S.,et al.(2006)Polymorphisms in TGF-betal gene and the risk of lung cancer.Lung Cancer(Amsterdam,Netherlands),52,1.
[12]Lee,K.M.,Park,S.K.,Hamajima,N.,Tajima,K.,Yoo,K.Y.,Shin,A.,et al.(2005)Genetic polymorphisms of TGF-betal & TNF-beta and breast cancer risk.Breast Cancer Research And Treatment,90,149.
[13]Sikolova,P.N.,Pawelec,G.P.,Mihailova,S.M.,Ivanova,M.I.,Myhailova,A.P.,Baltadjieva,D.N.,et al.(2007)Association of cytokine gene polymorphisms with malignant melanoma in Caucasian population.Cancer Immunology,Immunotherapy:CII,6,371.
[14]Crivello,A.,Giacalone,A.,Vaglica,M.,Scola,L.,Forte,G.I.,Macaluso,M.C.et al.(2006)Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma.Annals Of The New York Academy Of Sciences,1089,98.
[15]Kang HG,ChaeMH,Park JM,et al.Polymorphisms in TGF-betal gene and the risk of lung cancer.Lung Cancer(Amsterdam,Netherlands).2006;52:1-7.
[16]Stanczuk,G.A.,Tswana,S.A.,Bergstrom,S.,Sibanda,E.N.(2002)Polymorphism in codons 10 and 25 of the transforming growth factor-beta 1(TGF-betal)gene in patients with invasive squamous cell carcinoma of the uterine cervix.European Journal Of Immunogenetics:Official Journal OF The British Society For Histocompatibility And Immunogenetics,29,417.
[17]Stephens M,Smith NJ,Donnelly P.A new statistical method for haplotype reconstruction from population data.American Journal Of Human Genetics.2001;68:978-89.
[18]王建明 胃癌流行病学研究[J].中华肿瘤防治杂志,2006,13(1):1-7.
[19]Nyren O.Is Helicobacter pylori really the cause of cancer?[J].Semin Cancer Biol,1998,8(4):275-283
[20]Hansen S,Melby K K,Aase S,et al.Helicobacter pylo fection and risk of cardia cancer and non-cardia gastricer.A nested case-control study[J].Scand J Gastroen 1999,34(4):353-360.
[21]Takeuchi K,Ohno Y,Tsuzuki Y,et al.Helicobacter pylori infection and early gastric cancer[J].Br J Cancer,2001,85:1 147-152.
[22]Loffeld RILF,willems,Flendrg JA,et al.Helicobactry pylori and gastric carcinoma.Histopathology,1990,17(1):537-540.
[23]Go to T,Haruma K,Kitadai Y,et al Enhanced expression of inducible nitric oxide syntase and nitrotyrosine in gastric mucosa of gastric cancer patients[J].Clin Cancer Res,1999,5(6):1411-1415
[24]胡建鹏;赵玉亭;幽门螺杆菌与胃癌关系研究进展 医药论坛杂志。2007年6月第28卷 第12期 122-124.
[25]Chen JD,Keams S,Porter T,et al.MET mutation and familial gastric cancer.J Med Genet,2001,38(8):E26
[26]Yoshida,K.,Yokozaki,H.,Niimoto,M.,Ito,H.,Ito,M.,Tahara,E.(1989)Expression of TGF-beta and procollagen type Ⅰ and type Ⅲin human gastric carcinomas.International JournaJ Of Cancer.Journal International Du Cancer,44,394.
[27]EI-Omar EM,Carrington M,Chow WH et al.Interleukin-1polymorphisms associated with increased risk of gastric cancer J.Nature,2000,404(6776):398-402.
[28]何向民,姜莉,傅宝玉等。白细胞介素Ⅰβ及RN基因多态性与胃癌 易感性的关系J.中华医学杂志,2002,82(10):685-688.
[29]Wu MS,Huang SP,Chang YT et al.Tumor necrosis factor-alpha and interleukin-10 promoter polymorphisms in Epstein-Barr virus associated gastric carcinoma J.J Infect Dis,2002,185(1):106-109.
[30]Guo RJ,Wang Y,Kaneko E et al.Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type Ⅱ receptor gene in sporadic human gastric cancer J.Carcinogenesis,1998,19(9):1539-1544.
[31]Shibuta K,Mori M,Haraguchi M et al.Association between restriction fragment length polymorphism of the L-myc gene and susceptibility to gastric cancer.J.Surg,1998,85(5):681-684.
[32]Atsuko S,Julie P,Teri A et al.CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma J.Carcino genesis,2002,23(3):419-424.
[33]王晨 基因多态性与胃癌关系的研究进展[J].医学研究生报,2004,17(2):175-177.
[34]Lin,Y.,Kikuchi,S.,Obata,Y.,Yagyu,K.(2006)Serum levels of transforming growth factor betal are significantly correlated with venous invasion in patients with gastric cancer,Journal Of Gastroenterology And Hepatology 21,432.
[35]Yoshida,K.,Yokozaki,H.,Niimoto,M.,Ito,H.,Ito,M.,Tahara,E.(1989)Expression of TGF-beta and procollagen type Ⅰ and type Ⅲin human gastric carcinomas.International Journal Of Cancer.Journal International Du Cancer,44,394.
[36]Delarco J E et al.Proc NaH Acad Sci USA,1978;75;4001-4005
[37]Anzano MA et al.Proc NaH Acad Sci USA,1983;80:6264-6268.
[38]Gold LI.The role for transforming growth factor-beta(TGF-beta)in human cancer.Crit Rev Oncog,1999,10(4):303
[39]Park DY,Sol MY,Sub KS,et al.Expressions of transforming growth factor(TGF)-β1 and TGF-β1 type Ⅱ receptor and their relationship with apoptosis during chemical hepato—carcinogenesis in rats.Hepatol Res,2003,27(3):205-213.
[40]Gressner AM,Weiskirchen R,Breitkopf K,et al.Role of TGF-beta in hepatic fibrosis Front Biosci,2002,7:793-807
[41]Dery R,Feng XH.TGF-beta receptor signaling[J].Biochim Biophys Acta,1997,1333(2),F105-150.
[42]Taipale J,Saharinen J,Keski-ja J.Extracellular matrix-associated transforming growth factor-beta:role in cancer cell growth and invasion.[J].Adv Cancer Res,1998,75:87-134.
[43]Li X,Meng Y,Yang XS,et al.ACEI attenuates tile progression of CCI(4)—induced rat hepatic fibrogenesis by inhibiting TGF-betaI.PDGF-BB,NF-kappaB and MMP-2,9.World J Gastro-enterol,2005.Ⅱ(3I):4807-4811.
[44]Seharf JG,Braulke T.The role of the IGF axis in hepatocareinogenesi.Horm Metab Res,2003,35(11-12):685-693.
[45]Taniguchi H.Kato N,Otsuka M,et al.Hepatitis C virus core protein up-regulates transforming growth factor-βⅠ transcription.J Med Virol,2004,72(1):52-59.
[46]韦良宏,陈凤坤,谭宗群,陈海东 转化生长因子2β1基因多态性与结直肠癌关系的研究[J]肿瘤2007年5月第27卷第5期 TumorVol.27,No.5,May,2007 383-405
[47]Jin,Q.,Hemminki,K.,Grzybowska,E.,Klaes,R.,SSderberg,M.,Zientek,H.,et al.(2004)Polymorphisms and haplotype structures in genes for transforming growth factor betal and its receptors in familial and unselected breast cancers..International Journal Of Cancer.Journal International Du Cancer,112,94.
[48]Dunning,A.M.,Ellis,P.D.,McBride,S.,Kirschenlohr,H.L.,Healey,C.S.,Kemp,P.R.(2003)A transforming growth factorbetal signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer.Cancer Research,63,2610.
[49]唐任光,韦叶生,潘小炎 转化生长因子β1基因869T/C、915G/C多态性与食管癌关系的研究。[J]中华微生物学和免疫学杂志2006,26,5,468-471.
[50]Blobe,G.C.,Schiemann,W.P.,Lodish,H.F.(2000)Role of transforming growth factor beta in human disease.The New England Journal Of Medicine,342,1350.
[51]Fuccio,L.,Zagari,R.M.,Minardi,M.E.,Bazzoli,F.(2007)Systematic review:Helicobacter pylori eradication for the prevention of gastric cancer.Alimentary Pharmacology & Therapeutics,25,133.
[52]Malfertheiner,P.,Fry,L.C.,Monkemuller,K.(2006)Can gastric cancer be prevented by Helicobacter pylori eradication?Best Practice & Research.Clinical Gastroenterology,20,709。
[53]A zuma T,Takahash i T,Kunisato A,et al.Human CD4+ CD25+regulatory T cells suppress NKT cell function[J].Cancer Res,2003,63(15):4516-4520.
[54]Mitra R,Khar A.Suppression of macrophage function in A K-5 tumor transplanted animals:role of TGF-beta[J].Immunol Lett,2004,91(2-3):189-195.
[55]Bacchetta R,Sartirana C,Levings M K,et al.Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines[J].Eur J Immuno 1,2002,32(8):2237-2245.
[56]Castriconi R,Cantoni C,Chiesa MD,et al.Transforming growth factor-β1 inhibits expression of NKp30 and NKG2D receptors:Consequences for the NK-mediated killing of dendritic cells[J].Proc Natl Acad Sci USA,2003,100(7):4120-4125.
[2]Boesen,C.C.,Radaev,S.,Motyka,S.A.,Patamawenu,A.,Sun,P.D.(2002)The 1.1A crystal structure of human TGF-beta type Ⅱ receptor ligand binding domain.Structure,10,913.
[3]Florenes VA;Bhattacharya N;Bani MR;Ben-David Y;Kerbel RS;Slingerland JM(1996)TGF-beta mediated G1 arrest in a human melanoma cell line lacking p15INK4B:evidence for cooperation between p21Cip1/WAF1 and p27Kip1.Oncogene,13,2447.
[4]Wolfraim,L.A.,Walz,T.M.,James,Z.,Fernandez,T.,Letterio,J.J.(2004)P21cip 1 and P27kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2responsiveness.Journal Of Immunology(Baltimore,Md:1950),173,3093.
[5]Ziv,E.,Cauley,J.,Morin,P.A.,Saiz,R.,Browner,W.S.(2001)Association between the T29→C polymorphism in the transforming growth factor betal gene and breast cancer among elderly white women:The Study of Osteoporotic Fractures.JAMA:The Journal Of The American Medical Association 285,2859.
[6]Kim,S.S.,Shetty,K.,Katuri,V.,Kitisin,K.,Baek,H.J.,Tang,Y.,et al.(2006)TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer:role of the beta-spectrin,ELF.Biochemical and Biophysical Research Communications,344,1216.
[7]Derynck,R.,Akhurst,R.J.,Balmain,A.(2001)TGF-beta signaling in tumor suppression and cancer progression.Nature 6enetics,29,117.
[8]Derynck,R.,Zhang,Y.E.(2003)Smad-dependent and Smad-independent pathways in TGF-beta family signalling.Nature,425,577.
[9]Pasche,B.(2001)Role of transforming growth factor beta in cancer.Journal Of Cellular Physiology,186,153.
[10]Grainger DJ;Heathcote K;Chiano M;Snieder H;Kemp PR;Metcalfe JC;Carter ND;Specter TD.(1999)Genetic control of the circulating concentration of transforming growth factor type betal.Human Molecular Genetics 8,93.
[11]Kang,H.G.,Chae,M.H.,Park,J.M.,Kim,E.J.,Park,J.H.,Kam,S.,et al.(2006)Polymorphisms in TGF-betal gene and the risk of lung cancer.Lung Cancer(Amsterdam,Netherlands),52,1.
[12]Lee,K.M.,Park,S.K.,Hamajima,N.,Tajima,K.,Yoo,K.Y.,Shin,A.,et al.(2005)Genetic polymorphisms of TGF-betal & TNF-beta and breast cancer risk.Breast Cancer Research And Treatment,90,149.
[13]Sikolova,P.N.,Pawelec,G.P.,Mihailova,S.M.,Ivanova,M.I.,Myhailova,A.P.,Baltadjieva,D.N.,et al.(2007)Association of cytokine gene polymorphisms with malignant melanoma in Caucasian population.Cancer Immunology,Immunotherapy:CII,6,371.
[14]Crivello,A.,Giacalone,A.,Vaglica,M.,Scola,L.,Forte,G.I.,Macaluso,M.C.et al.(2006)Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma.Annals Of The New York Academy Of Sciences,1089,98.
[15]Kang HG,ChaeMH,Park JM,et al.Polymorphisms in TGF-betal gene and the risk of lung cancer.Lung Cancer(Amsterdam,Netherlands).2006;52:1-7.
[16]Stanczuk,G.A.,Tswana,S.A.,Bergstrom,S.,Sibanda,E.N.(2002)Polymorphism in codons 10 and 25 of the transforming growth factor-beta 1(TGF-betal)gene in patients with invasive squamous cell carcinoma of the uterine cervix.European Journal Of Immunogenetics:Official Journal OF The British Society For Histocompatibility And Immunogenetics,29,417.
[17]Stephens M,Smith NJ,Donnelly P.A new statistical method for haplotype reconstruction from population data.American Journal Of Human Genetics.2001;68:978-89.
[18]王建明 胃癌流行病学研究[J].中华肿瘤防治杂志,2006,13(1):1-7.
[19]Nyren O.Is Helicobacter pylori really the cause of cancer?[J].Semin Cancer Biol,1998,8(4):275-283
[20]Hansen S,Melby K K,Aase S,et al.Helicobacter pylo fection and risk of cardia cancer and non-cardia gastricer.A nested case-control study[J].Scand J Gastroen 1999,34(4):353-360.
[21]Takeuchi K,Ohno Y,Tsuzuki Y,et al.Helicobacter pylori infection and early gastric cancer[J].Br J Cancer,2001,85:1 147-152.
[22]Loffeld RILF,willems,Flendrg JA,et al.Helicobactry pylori and gastric carcinoma.Histopathology,1990,17(1):537-540.
[23]Go to T,Haruma K,Kitadai Y,et al Enhanced expression of inducible nitric oxide syntase and nitrotyrosine in gastric mucosa of gastric cancer patients[J].Clin Cancer Res,1999,5(6):1411-1415
[24]胡建鹏;赵玉亭;幽门螺杆菌与胃癌关系研究进展 医药论坛杂志。2007年6月第28卷 第12期 122-124.
[25]Chen JD,Keams S,Porter T,et al.MET mutation and familial gastric cancer.J Med Genet,2001,38(8):E26
[26]Yoshida,K.,Yokozaki,H.,Niimoto,M.,Ito,H.,Ito,M.,Tahara,E.(1989)Expression of TGF-beta and procollagen type Ⅰ and type Ⅲin human gastric carcinomas.International JournaJ Of Cancer.Journal International Du Cancer,44,394.
[27]EI-Omar EM,Carrington M,Chow WH et al.Interleukin-1polymorphisms associated with increased risk of gastric cancer J.Nature,2000,404(6776):398-402.
[28]何向民,姜莉,傅宝玉等。白细胞介素Ⅰβ及RN基因多态性与胃癌 易感性的关系J.中华医学杂志,2002,82(10):685-688.
[29]Wu MS,Huang SP,Chang YT et al.Tumor necrosis factor-alpha and interleukin-10 promoter polymorphisms in Epstein-Barr virus associated gastric carcinoma J.J Infect Dis,2002,185(1):106-109.
[30]Guo RJ,Wang Y,Kaneko E et al.Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type Ⅱ receptor gene in sporadic human gastric cancer J.Carcinogenesis,1998,19(9):1539-1544.
[31]Shibuta K,Mori M,Haraguchi M et al.Association between restriction fragment length polymorphism of the L-myc gene and susceptibility to gastric cancer.J.Surg,1998,85(5):681-684.
[32]Atsuko S,Julie P,Teri A et al.CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma J.Carcino genesis,2002,23(3):419-424.
[33]王晨 基因多态性与胃癌关系的研究进展[J].医学研究生报,2004,17(2):175-177.
[34]Lin,Y.,Kikuchi,S.,Obata,Y.,Yagyu,K.(2006)Serum levels of transforming growth factor betal are significantly correlated with venous invasion in patients with gastric cancer,Journal Of Gastroenterology And Hepatology 21,432.
[35]Yoshida,K.,Yokozaki,H.,Niimoto,M.,Ito,H.,Ito,M.,Tahara,E.(1989)Expression of TGF-beta and procollagen type Ⅰ and type Ⅲin human gastric carcinomas.International Journal Of Cancer.Journal International Du Cancer,44,394.
[36]Delarco J E et al.Proc NaH Acad Sci USA,1978;75;4001-4005
[37]Anzano MA et al.Proc NaH Acad Sci USA,1983;80:6264-6268.
[38]Gold LI.The role for transforming growth factor-beta(TGF-beta)in human cancer.Crit Rev Oncog,1999,10(4):303
[39]Park DY,Sol MY,Sub KS,et al.Expressions of transforming growth factor(TGF)-β1 and TGF-β1 type Ⅱ receptor and their relationship with apoptosis during chemical hepato—carcinogenesis in rats.Hepatol Res,2003,27(3):205-213.
[40]Gressner AM,Weiskirchen R,Breitkopf K,et al.Role of TGF-beta in hepatic fibrosis Front Biosci,2002,7:793-807
[41]Dery R,Feng XH.TGF-beta receptor signaling[J].Biochim Biophys Acta,1997,1333(2),F105-150.
[42]Taipale J,Saharinen J,Keski-ja J.Extracellular matrix-associated transforming growth factor-beta:role in cancer cell growth and invasion.[J].Adv Cancer Res,1998,75:87-134.
[43]Li X,Meng Y,Yang XS,et al.ACEI attenuates tile progression of CCI(4)—induced rat hepatic fibrogenesis by inhibiting TGF-betaI.PDGF-BB,NF-kappaB and MMP-2,9.World J Gastro-enterol,2005.Ⅱ(3I):4807-4811.
[44]Seharf JG,Braulke T.The role of the IGF axis in hepatocareinogenesi.Horm Metab Res,2003,35(11-12):685-693.
[45]Taniguchi H.Kato N,Otsuka M,et al.Hepatitis C virus core protein up-regulates transforming growth factor-βⅠ transcription.J Med Virol,2004,72(1):52-59.
[46]韦良宏,陈凤坤,谭宗群,陈海东 转化生长因子2β1基因多态性与结直肠癌关系的研究[J]肿瘤2007年5月第27卷第5期 TumorVol.27,No.5,May,2007 383-405
[47]Jin,Q.,Hemminki,K.,Grzybowska,E.,Klaes,R.,SSderberg,M.,Zientek,H.,et al.(2004)Polymorphisms and haplotype structures in genes for transforming growth factor betal and its receptors in familial and unselected breast cancers..International Journal Of Cancer.Journal International Du Cancer,112,94.
[48]Dunning,A.M.,Ellis,P.D.,McBride,S.,Kirschenlohr,H.L.,Healey,C.S.,Kemp,P.R.(2003)A transforming growth factorbetal signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer.Cancer Research,63,2610.
[49]唐任光,韦叶生,潘小炎 转化生长因子β1基因869T/C、915G/C多态性与食管癌关系的研究。[J]中华微生物学和免疫学杂志2006,26,5,468-471.
[50]Blobe,G.C.,Schiemann,W.P.,Lodish,H.F.(2000)Role of transforming growth factor beta in human disease.The New England Journal Of Medicine,342,1350.
[51]Fuccio,L.,Zagari,R.M.,Minardi,M.E.,Bazzoli,F.(2007)Systematic review:Helicobacter pylori eradication for the prevention of gastric cancer.Alimentary Pharmacology & Therapeutics,25,133.
[52]Malfertheiner,P.,Fry,L.C.,Monkemuller,K.(2006)Can gastric cancer be prevented by Helicobacter pylori eradication?Best Practice & Research.Clinical Gastroenterology,20,709。
[53]A zuma T,Takahash i T,Kunisato A,et al.Human CD4+ CD25+regulatory T cells suppress NKT cell function[J].Cancer Res,2003,63(15):4516-4520.
[54]Mitra R,Khar A.Suppression of macrophage function in A K-5 tumor transplanted animals:role of TGF-beta[J].Immunol Lett,2004,91(2-3):189-195.
[55]Bacchetta R,Sartirana C,Levings M K,et al.Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines[J].Eur J Immuno 1,2002,32(8):2237-2245.
[56]Castriconi R,Cantoni C,Chiesa MD,et al.Transforming growth factor-β1 inhibits expression of NKp30 and NKG2D receptors:Consequences for the NK-mediated killing of dendritic cells[J].Proc Natl Acad Sci USA,2003,100(7):4120-4125.