臺灣博碩士論文加值系統

過去我們的研究發現，抽菸、喝酒與嚼食檳榔都是食道癌的危險因子，而受幽門螺旋桿菌感染是食道癌的保護因子。但是還不清楚這些環境危險因子是如何影響食道癌的發生。

目的：本研究目的在探討發炎反應過程中佔有重要角色的細胞激素基因，如腫瘤壞死因子(TNFα-857)、介白素-1(IL1β-31)、介白素-1β拮抗因子(IL1 RN)的基因多型性與食道癌間的相關研究。

材料與方法：本研究設計採用醫院為主的病例對照研究法，從民國八十五年八月到九十五年四月，分別從高雄醫學大學附設中和紀念醫院與高雄榮民總醫院收集個案，共收集經由醫生診斷確定為新發生的鱗狀上皮細胞癌之食道癌患者223位為病歷組，其243位對照組來自相同醫院的健康檢查中心，並經由醫生診斷確定無癌症病史之個案，並以年齡 (±3歲) 及性別進行配對。利用聚合酶連鎖反應之方法判定腫瘤壞死因子(TNFα-857)、介白素-1(IL1β-31)、介白素-1β拮抗因子(IL1 RN)的基因型。

結果：本研究結果發現抽菸、喝酒與嚼食檳榔，會增加罹患食道癌的危險性；而感染幽門螺旋桿菌對於食道癌形成保護作用，會降低罹患食道癌的危險性。發炎相關細胞激素基因的基因多型性部份，在調整過可能的干擾因子之後，結果發現IL-1β-31帶TT基因型者相對於帶CC基因型者，罹患食道癌的危險性為1.59倍(95% CI, 0.67-3.78)；TNF-α-857帶TT基因型者相對於帶CC基因型者，罹患食道癌的危險性為1.16倍(95% CI, 0.67-3.78)；IL-1RN帶2R allele者相對於帶其他allele者，罹患食道癌的危險性為1.55倍(95% CI, 0.62-3.88)。基因與環境危險因子的交互作用部分，發現在沒有喝酒的人中，IL-1β-31帶TT基因型者相對於帶CC基因型者，罹患食道癌的危險性為4.15倍(95% CI, 0.97-17.84, p=0.055)。

結論：本研究結果顯示發炎相關細胞激素基因的基因多型性與罹患食道癌並無顯著之相關性，且發現環境危險因子與發炎相關細胞激素基因亦無交互作用關係。過去有研究發現食道癌的發生可能是因為氧化傷害(oxidative damage)所造成的，造成氧化傷害可能與胃食道逆流、抽菸或飲食有相關，但是胃食道逆流所引起的食道癌是以腺癌為主，故發炎相關細胞激素基因與罹患鱗狀上皮細胞癌之食道癌間的關係宜再進一步探討。

Our research group has found that cigarette smoke, alcohol consumption, and betel nut chewing are the risk factors for esophageal cancer. In contrast, H. pylori infection can protect form the development of esophageal cancer.

Objective: In this study, we investigated the association between the genetic polymorphism of inflammatory cytokine genes (TNFα-857, IL-1β-31 and IL-1RN) and esophageal cancer risks in the Taiwanese population.

Method: A hospital-based case-control study was conducted. Between August, 1996 and April, 2006, 223 newly-diagnosed esophageal squamous cell carcinoma and 243 controls were recruited from Kaohsiung Medical University Hospital (KMUH) and Kaohsiung Veterans General Hospital (KVGH). Controls were matched to the cases by age (±3 years) and sex. The TNFα-857, IL-1β-31 and IL-1RN polymorphisms were genotyped using a method of PCR-RFLP.

Results: In this study, we found increasing risk of cigarette smoking, alcoholic consumption and areca chewing on esophageal cancer risk. However, individuals with positive H. pylori infection had significantly effect to decrease esophageal cancer. After adjusted for appropriate covariates, individuals with IL-1β-31TT had a 1.59-fold risk (95% CI, 0.67-3.78) to develop esophageal cancer than those with IL-1β-31CT. Individuals with TNFα-857TT had a 1.16-fold risk (95% CI, 0.67-3.78) to develop esophageal cancer than those with TNFα-857CT. Individuals with IL-1RN 2R allele had a 1.55-fold risk (95% CI, 0.62-3.88) to develop esophageal cancer than those with IL-1RN other alleles.

Conclusion: Our results suggest polymorphisms of TNFα-857, IL-1β-31 and IL-1RN can’t modify the influence of inflammation on esophageal cancer risk. There was also no association between environmental hazards and genetic polymorphism of inflammatory cytokine genes on esophageal cancer risk. Some studies found that oxidative damage may induce esophageal cancer and the association between influence of inflammation and the risk of esophageal cancer may be relation to gastro-esophageal reflux disease, diet or smoking. Although gastro-esophageal reflux disease and adenocarcinoma esophageal cancer has been certified. Those results suggest that we need more evidence to discuss the relationship between esophageal cancer and inflammatory cytokine genes.

目錄
第一章 緒論 1
第一節 研究背景 1
第二節 研究動機 3
第二章 研究目的 4
第三章 文獻探討 5
第一節 食道癌 ( Esophageal cancer ) 5
第二節 環境危險因子與食道癌 ( Environmental hazards and Esophageal cancer) 5
一、 抽菸 6
二、 喝酒 7
三、 嚼食檳榔 8
四、 幽門螺旋桿菌 9
第三節 發炎相關細胞激素基因 ( Inflammatory cytokine genes ) 10
一、 介白素-1 ( Interleukin-1 ) 10
二、 腫瘤壞死因子 ( Tumor-necrosis factor-alpha, TNF-α ) 11
第四節 發炎相關細胞激素基因之基因多型性 ( Genetic polymorphism of Inflammatory cytokine genes ) 12
一、 介白素-1β ( Interleukin-1β, IL-1β ) 12
二、 介白素-1 接受器拮抗子 ( Interleukin-1 receptor antagonist, IL-1 RN ) 13
三、 腫瘤壞死因子 ( Tumor-necrosis factor-alpha, TNF-α) 15
第四章 材料與方法 16
第一節 研究架構 16
第二節 研究對象 16
一、 病例組 16
二、 對照組 17
第三節 問卷資料與血液檢體之收集 17
一、 問卷資料 17
二、 血液檢體之收集 18
第四節 實驗分析方法 18
一、 Genomic DNA萃取方法 18
二、 幽門螺旋桿菌測試方法 20
三、 基因多型性分析方法 20
四、 實驗室QA/QC 24
第五節 統計分析方法 25
第五章 結果 26
第一節 基本人口學特徵 26
第二節 抽菸、喝酒、嚼食檳榔習慣與食道癌之相關性 26
第三節 幽門螺旋桿菌感染與食道癌之相關性 28
第四節 發炎相關細胞激素基因多型性與食道癌之相關性 29
一、 介白素-1β ( Interleukin-1 beta, IL-1β ) 29
二、 介白素-1 接受器拮抗子 ( Interleukin-1 receptor antagonist, IL-1 RN ) 30
三、 腫瘤壞死因子 ( Tumor-necrosis factor-alpha, TNF-α) 30
第五節 環境危險因子與發炎相關細胞激素基因之交互作用分析 31
一、 抽菸 32
二、 喝酒 34
三、 嚼食檳榔 37
四、 幽門螺旋桿菌的感染 40
第六節 發炎相關細胞激素基因之間交互作用對於罹患食道癌的危險性分析 42
一、 介白素-1β與介白素-1接受器拮抗子(IL-1β-31&IL-1RN) 43
二、 介白素-1β與腫瘤壞死因子(IL-1β-31&TNFα-857) 43
三、 腫瘤壞死因子與介白素-1接受器拮抗子(TNFα-857& IL-1RN) 44
四、 腫瘤壞死因子與介白素-1β與介白素-1接受器拮抗子(TNFα-857&IL-1β-31&IL-1RN) 45
第六章 討論 47
第一節 研究方法與個案選取 47
第二節 發炎相關細胞激素基因與食道癌之相關性 48
一、 IL-1β-31與食道癌 48
二、 IL-1RN與食道癌 49
三、 TNFα-857與食道癌 50
第三節 環境因子與食道癌之相關性 51
第四節 發炎相關細胞激素基因與環境因子之交互作用 51
第五節 研究限制 52
第六節 結論 53
參考文獻 54
附件一 問卷內容

衛生署，2004
Barbara, J.A., Van ostade, X. and Lopez, A., 1996. Tumour necrosis factor-alpha (TNF-alpha): the good, the bad and potentially very effective. Immunol Cell Biol, 74(5): 434-43.
Chang, Y.W. et al., 2005. Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer. Int J Cancer, 114(3): 465-71.
Chitra, S., Ashok, L., Anand, L., Srinivasan, V. and Jayanthi, V., 2004. Risk factors for esophageal cancer in Coimbatore, southern India: a hospital-based case-control study. Indian J Gastroenterol, 23(1): 19-21.
Dinarello, C.A., 1996. Biologic basis for interleukin-1 in disease. Blood, 87(6): 2095-147.
Eigler, A., Sinha, B., Hartmann, G. and Endres, S., 1997. Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol Today, 18(10): 487-92.
El-Omar, E.M., 2001. The importance of interleukin 1beta in Helicobacter pylori associated disease. Gut, 48(6): 743-7.
El-Omar, E.M. et al., 2000. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature, 404(6776): 398-402.
Guo, W., Wang, N., Li, Y. and Zhang, J.H., 2005. Polymorphisms in tumor necrosis factor genes and susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in a population of high incidence region of North China. Chin Med J (Engl), 118(22): 1870-8.
Hajeer, A.H. and I.V. Hutchinson., 2000. TNF-alpha gene polymorphism: clinical and biological implications. Microsc Res Tech, 50:216-28.
He, X., Jiang, L., Fu, B. and Zhang, X., 2002. [Relationship between interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms and susceptibility to gastric cancer]. Zhonghua Yi Xue Za Zhi, 82(10): 685-8.
Hsu, P.I. et al., 2004. The interleukin-1 RN polymorphism and Helicobacter pylori infection in the development of duodenal ulcer. Helicobacter, 9(6): 605-13.
Hung, H.C. et al., 2004. Association between diet and esophageal cancer in Taiwan. J Gastroenterol Hepatol, 19(6): 632-7.
Iizuka, N. et al., 1999. Interleukin-1 receptor antagonist mRNA expression and the progression of gastric carcinoma. Cancer Lett, 142(2): 179-84.
Ito, L.S. et al., 2002. Significant reduction in breast cancer risk for Japanese women with interleukin 1B -31 CT/TT relative to CC genotype. Jpn J Clin Oncol, 32(10): 398-402.
Koivurova, O.P. et al., 2003. IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients. Scand J Gastroenterol, 38(12): 1217-22.
Launoy, G., Milan, C., Faivre, J., Pienkowski, P. and Gignoux, M., 2000. Tobacco type and risk of squamous cell cancer of the oesophagus in males: a French multicentre case-control study. Int J Epidemiol, 29(1): 36-42.
Lee, C.H. et al., 2005. Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan. Int J Cancer, 113(3): 475-82.
Lee, K.M., Yoo, K.Y., Choi, J.Y. and Ahn , S.H., 2006. Genetic polymorphism of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) and breast cancer risk in Korean women. Breast Cancer Research and Treatment, 96: 197-202.
Lee, S.G. et al., 2004. TNF/LTA polymorphisms and risk for gastric cancer/duodenal ulcer in the Korean population. Cytokine, 28(2): 75-82.
Montecucco, C. and Rappuoli, R., 2001. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat Rev Mol Cell Biol, 2(6): 457-66.
Moons, L.M., Siersema, P.D., Kuipers, E.J., van Vliet, A.H. and Kusters, J.G., 2005. IL-1 RN polymorphism is not associated with Barrett''s esophagus and esophageal adenocarcinoma. Am J Gastroenterol, 100(12): 2818.
Nishimura, M. et al., 2003. TNF, TNF receptor type 1, and allograft inflammatory factor-1 gene polymorphisms in Japanese patients with type 1 diabetes. Hum Immunol, 64(2): 302-9.
Ohyama, I. et al., 2004. The association between tumour necrosis factor-alpha gene polymorphism and the susceptibility to rugal hyperplastic gastritis and gastric carcinoma. Eur J Gastroenterol Hepatol, 16(7): 693-700.
Palli, D. et al., 2005. Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population. Am J Gastroenterol, 100(9): 1941-8.
Parkinson, D.R., 1989. Cytokines in cancer therapy. Urology, 34(4 Suppl): 69-74; discussion 87-96.
Robert, A., Olafsson, A.S., Lancaster, C. and Zhang, W.R., 1991. Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach, and retards gastric emptying. Life Sci, 48(2): 123-34.
Rollinson, S. et al., 2003. Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood, 102(3): 1007-11.
Saito, S. et al., 2001. Polymorphism of tumor necrosis factor in esophageal, gastric or colorectal carcinoma. Hepatogastroenterology, 48(38): 468-70.
Sakata, K. et al., 2005. Smoking, alcohol drinking and esophageal cancer: findings from the JACC Study. J Epidemiol, 15 Suppl 2: S212-9.
Santtila, S., Savinainen, K. and Hurme, M., 1998. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol, 47(3): 195-8.
Sasco, A.J., Secretan, M.B. and Straif, K., 2004. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer, 45 Suppl 2: S3-9.
Schulte, T. et al., 2002. Polymorphisms in the interleukin-1 alpha and beta genes and the risk for Parkinson''s disease. Neurosci Lett, 326(1): 70-2.
Soga, Y. et al., 2003. Tumor necrosis factor-alpha gene (TNF-alpha) -1031/-863, -857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol, 30(6): 524-31.
Tarlow, J.K. et al., 1993. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet, 91(4): 403-4.
Terry, P., Lagergren, J., Ye, W., Nyren, O. and Wolk, A., 2000. Antioxidants and cancers of the esophagus and gastric cardia. Int J Cancer, 87(5): 750-4.
Tseng L.H., Chen P.J., Lin M.T. et al., 2001. Single nucleotide polymorphisms in intron2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene: further definition of the IL-1 beta and IL-1 Ra polymorphisms in North American Caucasians and Taiwanese Chinese. Tissue Antigens; 57:318-24.
Tsuchiya, N. et al., 2004. Influence of TNF gene polymorphism in patients with acute and fulminant hepatitis. J Gastroenterol, 39(9): 859-66.
van Heel, D.A. et al., 2002. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. Hum Mol Genet, 11(11): 1281-9.
Vassalli, P., 1992. The pathophysiology of tumor necrosis factors. Annu Rev Immunol, 10: 411-52.
Wu, D.C. et al., 2005. Helicobacter pylori infection: a protective factor for esophageal squamous cell carcinoma in a Taiwanese population. Am J Gastroenterol, 100(3): 588-93.
Wu, I.C. et al., 2006a. Interaction between cigarette, alcohol and betel nut use on esophageal cancer risk in Taiwan. Eur J Clin Invest, 36(4): 236-41.
Wu, M. et al., 2006b. Association of smoking, alcohol drinking and dietary factors with esophageal cancer in high- and low-risk areas of Jiangsu Province, China. World J Gastroenterol, 12(11): 1686-93.
Wu, M.S. et al., 2004. Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma. Int J Cancer, 110(5): 695-700.
Yang, J. et al., 2004. Interleukin-1B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population. Cancer Lett, 215(2): 191-8.
Zambon, C.F. et al., 2005. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine, 29(4): 141-52.
Zienolddiny, S. et al., 2004. Polymorphisms of the interleukin-1 beta gene are associated with increased risk of non-small cell lung cancer. Int J Cancer, 109(3): 353-6.