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研究生:朱殷弘
研究生(外文):Yin-Hung
論文名稱:類胰島素生長因子及其相關基因之基因多型性與肝細胞癌之相關性探討
論文名稱(外文):Association of polymorphism of insulin-like growth factor genes with susceptibility to and severity of hepatocellular carcinoma
指導教授:楊順發
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:77
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中文摘要
肝細胞癌是世界各地因癌症死亡的主要原因之一。而在肝癌初期並無明顯的症狀,因此導致罹患肝細胞癌的患者不易察覺而延誤了就醫時間。類胰島素生長因子(insulin-like growth factor; IGF)在過去被認為與細胞的增生與分化有關,因此被認為與嬰幼兒的生長遲緩有關。然而在近年來的研究中更指出,透過一連串的訊息傳遞之後,類胰島素生長因子能夠同時藉由刺激細胞增生以及抑制細胞凋亡的機制,誘使細胞走向癌化。所以在本研究中藉由102位肝細胞癌的患者以及306位健康對照者進行性別年齡的配對後,利用其DNA檢體以聚合酶連鎖反應-限制酶切割片段多型性技術(PCR-RFLP)以及即時定量聚合酶連鎖反應(real-time PCR)進行對於IGF家族中IGF-1、IGF-2、IGF-1R、IGF-2R以及類胰島素生長因子結合蛋白-3(IGFBP-3)和人類胰島素基因(INS)等基因分析其基因多型性。結果中發現,在IGF-2 +3580位置上的變異在肝癌病例與健康對照組間基因頻率的分佈具有顯著差異(P=0.02)。而在多變項回歸模式中的結果顯示IGF-2R基因攜帶AA或AG基因型能夠保護避免C型肝炎的發生(OR=0.35; 95%CI=0.15-0.82)。同時在加入了IGF-2與IGF-2R探討其中基因與基因交互作用後也發現,若是IGF-2R擁有正常與IGF-2結合的能力,能夠降低保護個體罹患肝細胞癌的危險(OR=0.20; 95%CI=0.05-0.87)。在本研究中雖然觀察到攜帶IGF-2 +3580 AA基因型對於肝細胞癌的發生有一個直接的相關,而且IGF-2R在其中也扮演了一個重要的角色。然而,肝細胞癌的發生可能是由多種環境因子合併生理因子所造成。因此,基因對癌症所造成的相關影響可能也會受到環境因子所調控,而這需要更完整的流行病學資料加以分析及討論。


Abstract
Hepatocellular carcinoma is one of the major causes of cancer death worldwide. Due to the absence of significant symptoms during the early stage, patients may be unaware of the disease without seeking medical advice. Based on its associated with cell proliferation and differentiation, insulin-like growth factor (IGF) has been reported to be related with growth retardation of newborns. Recent studies indicated that IGF may stimulate several signal pathways to induce cell proliferation and inhibit cell apoptosis, leading to the transformation of normal cells to cancer cells. In this case-control study, a total of 102 hepatocellular carcinoma patients and 306 age- and gender- matched controls were recruited. Their genomic DNA samples were subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR genotyping analysis to analyze the genetic polymorphisms of several genes, include IGF-1, IGF-2, IGF-1R, IGF-2R, IGF binding protein (IGFBP-3) and INS gene. Results indicated that there was a significant difference in the distribution frequency of IGF-2 +3580 polymorphism between case and control group (P=0.02). Results from multiple regression model showed that the presence of AA or AG at IGF-2R may has a potentially protection effect from hepatitis C (OR=0.35; 95%CI=0.15-0.82). After considered gene and gene interaction, we found there is an interaction between IGF-2 and IGF-2R genes. It shows if IGF-2R keep the binding abilities to IGF-2, it comes a protection effect from hepatocellular carcinoma (OR=0.20; 95%CI=0.05-0.87). Although, this study has revealed a close association between IGF-2 GG genotype and the risk of hepatocellular carcinoma, also IGF-2R may take turns in it. However, the occurrence of hepatocellular carcinoma may be influenced by various environmental risk factors and physiological factors. Therefore, further and more detailed epidemiology and molecular studies should be conducted to investigate the association between these genetic polymorphisms and the risk of cancers.


目錄
中英文摘要 ……………………………………………………………3
壹、緒論 ………………………………………………………………7
貳、研究動機 …………………………………………………………28
叁、實驗材料與方法 …………………………………………………29
肆、實驗結果 …………………………………………………………35
伍、討論 ………………………………………………………………40
陸、參考文獻 …………………………………………………………45
柒、圖表與圖表說明 …………………………………………………55


陸、參考文獻
1.Harzke AJ, Baillargeon JG, Goodman KJ, Pruitt SL. Liver cancer mortality among male prison inmates in Texas, 1992–2003. Prev Med. 2009; available online 13 March.

2.Yu MW, Chen CJ. Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol. 1994; 17: 71-91.

3.Alencar RS, Gomes MM, Sitnik R, Pinho JR, Malta FM, Mello IM, Mello ES, Bacchella T, Machado MC, Alves VA, Carrilho FJ. Low occurrence of occult hepatitis B virus infection and high frequency of hepatitis C virus genotype 3 in hepatocellular carcinoma in Brazil. Braz J Med Biol Res. 2008; 41: 235-240.

4.Yeh CN, Chen MF, Lee WC, Jeng LB. Prognostic Factors of Hepatic Resection for Hepatocellular Carcinoma with Cirrhosis: Univariate and Multivariate Analysis. J Surg Oncol. 2002; 81: 195–202.

5.Yu MC, Yuan JM. Environmental Factors and Risk for Hepatocellular Carcinoma. Gastroenterology. 2004; 127: S72–S78.

6.Asmaa IG, Shahid AK, Edward LL, Imam W, Simon D. Diagnosis of hepatocellular carcinoma. World J Gastroenterol. 2008; 15: 1301-1314.

7.Morris-Stiff G, Gomez D, Carino N de Liguori, Prasad KR. Surgical management of hepatocellular carcinoma: Is the jury still out? Surg Oncol. 2008; accepted 19 August

8.Kazuto I, Takayuki N, Taira K, Masaru K, Toshio N, Tatsuya O, Shinichiro T, Naoto G, Takayuki H, Shigeru N. Volume reduction surgery for advanced hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004; 130: 362-366.

9.Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005. J Clin Oncol. 2009; 27: 1485-1491.

10.Grimberg A, Cohen P. Role of Insulin-Like Growth Factors and Their Binding Proteins in Growth Controland Carcinogenesis. J Cell Physiol. 2000; 183: 1–9.

11.Rene EH. Insulin-like growth factors I and II. Eur J Biochem. 1990; 190: 445-462.

12.Carel JC, Chaussain JL, Chatelain P, Savage MO. Growth hormone insensitivity syndrome (Laron syndrome): main characteristics and effects of IGF1 treatment. Diabetes Metab. 1996; 22: 251-6.

13.Vincent HH, Marc AD, Wim AB. Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation. Cytokine Growth Factor Rev. 1999; 10: 5-14.

14.Delafontaine P, Song YH, Li Y. Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels. Arterioscler Thromb Vasc Biol. 2004; 24: 435-444.

15.Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 2008; 6: 821-833.

16.Cleveland RJ, Gammon MD, Edmiston SN, Teitelbaum SL, Britton JA, Terry MB, Eng SM, Neugut AI, Santella RM, Conway K. IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project. Carcinogenesis. 2006; 27: 758–765.

17.Cheng I, Stram DO, Penney KL, Pike M, Le Marchand L, Kolonel LN, Hirschhorn J, Altshuler D, Henderson BE, Freedman ML. Common Genetic Variation in IGF1 and Prostate Cancer Risk in the Multiethnic Cohort. J Natl Cancer Inst. 2006; 98: 123-34.

18.Tao Y, Pinzi V, Bourhis J, Deutsch E. Mechanisms of Disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer. Nat Clin Pract Oncol. 2008; 4: 591-602.

19.Ester WA, Hokken K. Polymorphisms in the IGF1 and IGF1R genesand children born small for gestational age: results of large population studies. Best Pract Res Clin Endocrinol Metab. 2008; 22:415-431.

20.Roldan MB, White C, Witchel SF. Association of the GAA1013→GAG polymorphism of the insulin-like growth factor-1 receptor (IGF1R) gene with premature pubarche. Fertil Steril. 2007; 88: 410 –7.

21.Deming SL, Ren Z, Wen W, Shu XO, Cai Q, Gao YT, Zheng W. Genetic variation in IGF1, IGF-1R, IGFALS, and IGFBP3 in breast cancer survival among Chinese women: a report from the Shanghai Breast Cancer Study. Breast Cancer Res Treat. 2007; 104: 309-319.

22.Cooper WN, Curley R, Macdonald F, Maher ER. Mitotic recombination and uniparental disomy in Beckwith-Wiedemann syndrome. Genomics. 2007; 89: 613-617

23.Chao W, D''Amore PA. IGF2: Epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 2008; 19: 111-120.

24.Kaku K, OsadH a, Seki K, Sekiya S. Insulin-like growth factor 2 (IGF2) and IGF2 receptor gene variants are associated with fetal growth. Acta Pædiatrica. 2007; 96: 363-367.

25.Gomes MV, Soares MR, Pasqualim-Neto A, Marcondes CR, Lôbo RB, Ramos ES. Association between birth weight, body mass index and IGF2/ApaI polymorphism. Growth Horm IGF Res. 2005; 15: 360-362.

26.Ho GY, Melman A, Liu SM, Li M, Yu H, Negassa A, Burk RD, Hsing AW, Ghavamian R, Chua SC Jr. Polymorphism of the insulin gene is associated with increased prostate cancer risk. Br J Cancer. 2003; 88: 263-269.

27.DaCosta SA, Schumaker LM, Ellis MJ. Mannose 6-phosphate/insulin-like growth factor 2 receptor, a bona fide tumor suppressor gene or just a promising candidate? J Mammary Gland Biol Neoplasia. 2000; 5: 85-94.

28.Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev. 2005; 16: 421-439.

29.Pavelic J, Radakovic B, Pavelic K. Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma. Gynecol Oncol. 2007; 105: 727-735.

30.Kotsinas A, Evangelou K, Sideridou M, Kotzamanis G, Constantinides C, Zavras AI, Douglass CW, Papavassiliou AG, Gorgoulis VG. The 3’ UTR IGF2R-A2/B2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer. Cancer Lett. 2008; 259: 177-185.

31.Jang HS, Kang KM, Choi BO, Chai GY, Hong SC, Ha WS, Jirtle RL. Clinical significance of loss of heterozygosity for M6P/IGF2R in patients with primary hepatocellular carcinoma. World J Gastroenterol. 2008; 14: 1394-1398.

32.Rezgui D, Williams C, Savage SA, Prince SN, Zaccheo OJ, Jones EY, Crump MP, Hassan AB. Structure and function of the human Gly1619Arg polymorphism of M6P/IGF2R domain 11 implicated in IGF2 dependent growth. J Mol Endocrinol. 2009; 42: 341-56.

33.London SJ, Yuan JM, Travlos GS, Gao YT, Wilson RE, Ross RK, Yu MC. Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China. J Natl Cancer Inst. 2002; 94: 749-54.

34.Schedlich LJ, Graham LD. Role of Insulin-Like Growth Factor Binding Protein-3 in Breast Cancer Cell Growth. Microsc Res Tech. 2002; 59:12–22.

35.Cohen P. Insulin-like growth factor binding protein-3: insulin-like growth factor independence comes of age. Endocrinology. 2006; 147: 2109-11.

36.Hoyo C, Grubber J, Demark-Wahnefried W, Marks JR, Freedland SJ, Jeffreys AS, Grambow SC, Wenham RM, Walther PJ, Schildkraut JM. Grade-specific prostate cancer associations of IGF1 (CA)19 repeats and IGFBP3-202A/C in blacks and whites. J Natl Med Assoc. 2007; 99: 718-22.

37.Costalonga EF, Antonini SR, Guerra-Junior G, Mendonca BB, Arnhold IJ, Jorge AA. The -202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency. J Clin Endocrinol Metab. 2009; 94: 588-95.

38.Pugliese A, Miceli D. The insulin gene in diabetes. Diabetes Metab Res Rev. 2002; 18: 13-25.

39.Claeys GB, Sarma AV, Dunn RL, Zuhlke KA, Beebe-Dimmer J, Montie JE, Wojno KJ, Schottenfeld D, Cooney KA. INSPstI polymorphism and prostate cancer in African-American men. Prostate. 2005; 65: 83-7.

40.Sarita B; Nagpal JK; Khadapkar R; Das BR; Evaluating the association between type-2 diabetes and polymorphisms at +1127 INS–PstI and +3580 IGF-II–MspI locus. Curr Sci. 2005; 89: 535-539

41.Petry CJ, Ong KK, Wingate DL, Brown J, Scott CD, Jones EY, Pembrey ME, Dunger DB; Alspac Study Team. Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height. Growth Horm IGF Res. 2005; 15: 363-8.

42.Wu X, Yu H, Amos CI, Hong WK, Spitz MR. Joint effect of insulin-like growth factors and mutagen sensitivity in lung cancer risk. J Natl Cancer Inst. 2000; 92: 737-43.

43.Ren Z, Cai Q, Shu XO, Cai H, Li C, Yu H, Gao YT, Zheng W. Genetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women. Cancer Epidemiol Biomarkers Prev. 2004; 13: 1290-5.

44.Wang L, Habuchi T, Tsuchiya N, Mitsumori K, Ohyama C, Sato K, Kinoshita H, Kamoto T, Nakamura A, Ogawa O, Kato T. Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer. Cancer Res. 2003; 63: 4407-11.

45.Schernhammer ES, Hankinson SE, Hunter DJ, Blouin MJ, Pollak MN. Polymorphic variation at the -202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk. Int J Cancer. 2003; 107: 60-4.

46.Deal C, Ma J, Wilkin F, Paquette J, Rozen F, Ge B, Hudson T, Stampfer M, Pollak M. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab. 2001; 86: 1274-80.

47.Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Analysis of 606 patients. Cancer. 1989; 64: 1700-7.

48.Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008; 8: 915-28.

49.Kaneda A, Wang CJ, Cheong R, Timp W, Onyango P, Wen B, Iacobuzio-Donahue CA, Ohlsson R, Andraos R, Pearson MA, Sharov AA, Longo DL, Ko MS, Levchenko A, Feinberg AP. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc Natl Acad Sci U S A. 2007; 104: 20926-31.

50.Shevah O, Laron Z. Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res. 2007; 17: 54-7.

51.Dziadziuszko R, Camidge DR, Hirsch FR. The insulin-like growth factor pathway in lung cancer. J Thorac Oncol. 2008; 3: 815-8.

52.Chao W, D''Amore PA. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 2008; 19: 111-20.

53.Jacobs CI. A review of the role of insulin-like growth factor 2 in malignancy and its potential as a modifier of radiation sensitivity. Clin Oncol (R Coll Radiol). 2008; 20: 345-52.

54.Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Müller U, Samson E, Quintanilla-Martinez L, Zimmer A. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem. 2000; 275: 28341-4.

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