第四章 討論
第三節 研究限制以及未來的展望
在這本研究中有很多的限制，例如：我們的病人數目太少且集中在台灣的
中部。我們的資料可能屬於有限的數值，因此聯合台灣各大醫學中心以增加更多
病患對研究是必要的。但我們不能確定增加病患數目後能發現IL-2R C/T 基因多
型性與前列腺癌之間有明顯的關連。不過，在看少的樣本數目時，必須記住Type
II 錯誤的可能性。另外絕對不能忽略人種的差異。
前列腺癌病人的IL-2 基因 C/T 或 IL-2R 基因 G/T 多型性對存活的時間並沒
有明顯的差異。未來的研究應批准把存活時間延長超過十年，或許就可以看出差
異。就結果來說IL-2 基因 C/T 及 CDH-1 3’-UTR C/T 基因多型性與前列腺癌有
關，且能把這個基因當作是研究前列腺癌腫瘤新生的一個可能的遺傳標記。這樣
我們需要對帶有此種基因多型性的人群訂下更嚴格之前列腺癌之篩選時間及條
件；或更能早期發現及找對方法治療前列腺癌。
參考文獻
1. 于大雄，張聖原、馬正平：中華民國台灣省泌尿道惡性腫瘤死亡率之變 (DOH82-HP-123-4M17).行政院衛生署,1993.
5. 陳 黎 明 , 江 金 培 , 黃 俊 雄 ：前 列 腺 癌 ： 42 例 之 分 析. 臺 灣 醫 誌 1990.89:238-41.
6. 王約翰: 前列腺癌之臨床病理研究.國防醫學院醫學研究所碩士論文 1985.
7. Wu TT, Chen KK, Chen MT, Huang JK, Chang LS: Distribution of distant metastases in patients with advanced adeno-carcinoma of the prostate. J Urol ROC,1993.4: 985-990.
8. Fan K, Peng CF: Histological grading of carcinoma of prostate in predicting the probability of bone metastasis: A retrospective correlative analysis of 72 autopsy cases with antemortem TUR-Prostate specimen. 長 庚 醫 學,1982.5:236-42.
9. Hsu YS, Chen KK, Chen MT, Huang JK, Lin ATL, Lee YH, Chang YH, Chang LS: The pelvic lymph nodes metastasis in cancer of prostate-preliminary report. J Urol ROC, 1992.2: 682-687.
10. 何偉宗,賴達三,勞漢信,丘祖毅,蔡宗璋,王經綸,許德金,謝有福,江萬煊:前列 腺惡性腫瘤之十二年報告.中華民國外科醫學會雜誌,1978.11(2): 120-25.
11. Lin BH, Hsiao IJ, Lee SH, Kuo HT, Lee MJ, Lee SH, Chen HC, Huang TW:
Squamous cell crcinoma of the prostate. J Urol ROC,1992.2: 722-27.
12. 李維菁,陳光國,陳明村,張心湜: 根除性攝護腺癌切除的臨床經驗.中華 泌尿醫學會年會摘要, 1992.A29: 77.
13. Wu CCJ, Lai MK, Lin CC: Urethral suture guide using a Foley catheter and a wire stylet for radical prostatectomy or cystoprostatectomy. J Surg Assoc ROC,1993.26: 1541-44.
14. 劉文山,吳永平: 攝護腺癌的放射治療. 臨床醫學,1990.26: 265-270.
15. 張樹人, Good J, Kassabian VS: 攝護腺癌經放射線治療後以血中攝護腺 癌特異性抗原測其疾病之惡化. 中華泌尿醫學會年會摘要,1993.A43: 79.
16. Chiu TY, Huang HS, Chen J, Law HS, Hsieh TS, Chen SC, Hsieh JT, Yu HJ, Lin MC, Lin SP, Wang CJ: Prostate Cancer: retrospective comparison of digital rectal examination,transrectal ultrasonography and prostate-specific antigen. J Urol ROC,1993.4: 1206-1211.
17. Birchmeier W, Behrens J: Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta,1994. 1198(1): 11-26.
18. Okegawa T, Pong RC, Li Y, Hsieh JT: The role of cell adhesion molecule in cancer progression and its application in cancer therapy. Acta Biochim Pol,2004. 51(2): 445-457.
19. Aberle H, Schwartz H, Kemler R: Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem,1996. 61(4): 514-523.
20. Hsu YS, Wang JS, Wu TT: E-cadherin expression in prostate adenocarcinomas in Chinese and its pathological correlates. Urol Int,2004.3(1): 36-40.
21. Krill D, Thomas A, Wu SP, Dhir R, Becich MJ: E-cadherin expression and PSA secretion in human prostate epithelial cells. Urol Res,2001.29(4):
287-292.
22. Shimoyama Y, Hirohashi S, Hirano S, Noguchi M, Shimosato Y, Takeichi M, Abe O: Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res, 1989.49(8): 2128-2133.
23. Gumbiner BM: Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell, 1996.84(3): 345-357.
24. Harington KJ, Syrigos KN: The role of E-cadherin-catenin complex: more than an intercellular glue? Ann Surg Oncol, 2000.7(10): 783-788
25. Becker KF, Reich U, Schott C, Hofler H: Single nucleotide polymorphisms in the human E-cadherin gene. Hum Genet, 1995. 96(6): 739-740.
26. Tsai FJ, Wu HC, Chen HY, Lu HF, Hsu CD, Chen WC: Association of
E-cadherin gene 3'-UTR C/T polymorphism with calcium oxalate stone disease. Urol Int,2003.70(4): 278-281.
27. Horak I: Immunodeficiency in IL-2-knockout mice. Clin Immunol Immunopathol, 1995.76: S172-S173.
28. Matesanz F, Fedetz M, Collado-Romero M, Fernandez O, Guerrero M, Delgado C, Alcina A: Allelic expression and interleukin-2
polymorphisms in multiple sclerosis. J Neuroimmunol,2001.119(1):
101-105.
29. Sadlack B, Lohler J, Schorle H, Klebb G, Haber H, Sickle E, Noelle RJ, Horak I: Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol, 1995.25(11): 3053-3059.
30. McCarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A, Southgate C, Easton DF, Eeles RA, Howell WM. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res,2002.62(12): 3369-3372
31. Harris DT, Matyas GR, Gomella LG, Taylor E,Winship MD, Spitler LE, Mastrangelo MJ: Immunologic approaches to the treatment of prostate cancer.
Semin Oncol, 1999.26(4): 439-447.
32. Dolman CS, Mueller BM, Lode HN, Xiang R, Gillies SD, Reisfeld RA:
Suppression of human prostate carcinoma metastases in severe combined immunodeficient mice by interleukin 2 immunocytokine therapy. Clin Cancer Res, 1998.4(10): 2551-2557.
33. Royuela M, De Miguel MP, Bethencourt FR, Frail B, Arenas MI, Paniagua R:
IL-2, its receptors, and bcl-2 and bax genes in normal, hyperplastic and carcinomatous human prostates: immunohistochemical comparative analysis.
Growth Factors, 2000.18(2): 135-146.
34. Matesanz F, Alcina A: Induction of autoantibodies to different interleukin-2 allotypes. J Autoimmun, 1999.12(3): 221-227.
35. Matesanz, F, Alcina A, Pellicer A: A new cDNA sequence for the murine interleukin-2 gene. Biochim Biophys Acta, 1992.1132(3): 335-336.
36. Matesanz, F, Alcina A, Pellicer A: Existence of at least five interleukin-2 molecules in different mouse strains. Immunogenetics, 1993.38(4): 300-303.
37. Matesanz F, Delgado C, Fresno M, Alcina A: Allelic selection of human IL-2 gene. Eur J Immunol, 2000.30(12): 3516-3521.
38. 王署奎,王自正,黃宇烽:單核苷酸多型性與前列腺癌關係的研究進展.中華 男科學雜誌,2005.11(8):605-610.
39. Gleason DF: Classification of prostatic carcinomas. Cancer Chemother Rep, 1966.50: 125-128.
40. Gleason DF, Mellinger GT: Prediction of prognosis for prostatic
adenocarcinoma by combined histological grading and clinical staging. J Urol, 1974.11: 58-64.
41. Aus G, Abbou CC, Pacik D, Schmid HP, vanPoppel H, Wolff JM, Zattoni F:
EAU guidelines on prostate cancer. Eur Urol, 2001.40(2): 97-101.
42. Lee YH, Huang WC, Tsai JY, Lu CM, Chen WC, Lee MH, Hsu HS, Huang JK, Chang LS: Epidemiological studies on the prevalence of upper urinary calculi in Taiwan. Urol Int, 2002.68(3): 172-177.
43. Takeichi M: Cadherin in cancer: implications for invasion and metastasis.
Curr Opin Cell Biol,1993.5: 806-811,
44. Mareel M,Bracke M, Van-Roy F: Invasion promoter versus invasion suppressor molecules: the paradigm of e-cadherin. Mol Biol Rep,1994.19:
45-47.
45. Karatzas G, Karayiannakis AJ, Syrigos KN,Chatzigianni E, Papanikolaou S, Riza F, Papanicolaou D: E-cadherin expression correlates with tumor differentiation on colorectal cancer. HepatoGastroenterology,1999.46:
232-235.
46. Seery JP, Syrigos KN, Karayiannannakis AJ, Valizadeh A, Pignatelli M:
Abnormal expression of the E-cadherin-catenin complex in dysplastic Barrett’s oesophagus. Acta Oncol,1999.38: 945-948.
47. Syrigos KN, Harrington K, Waxman J, Krausz T, Pignatelli M: Altered γ -catenin expression correlates with poor survival in patients with bladder cancer. J Urol,1998.160: 1889-1893.
48. Gumbiner BM, McCrea PD: Catenin as mediators of the cytoplasmic functions of cadherins. J Cell Sci,1993.17: 155-158.
49. Kuefer R, Hofner MD, Gschwend JE, Pienta KJ, Sanda MG, Chinnaiyan AM,
Rubin MA, Day ML: The role of an 80 kDa fragment of E-cadherin in the metastatic progression of prostate cancer. Clin Cancer Res,2003.9(17):
6447-6452.
50. Chunthapong J, Seftor EA, Khalkhali-Ellis Z, Seftor RE, Amir S, Lubaroff DM, Heidger PM, Hendrix MJC: Dual roles of E-cadherin in prostate cancer invasion. J Cell Biochem,2004.91(4): 649-661.
51. Beaveon IRG. Regulation of E-cadherin: dose hypoxia initiate the metastasis cascade? J Clin Pathol: Mol Pathol,1999.52: 179-188.
52. Verhage BA, van Houwelingen K, Ruijter TE, Kiemeney LA, Schalken JA:
Single-nucleotide polymorphism in the E-cadherin gene promoter modifies the risk of prostate cancer. Int J Cancer,2002.100(6): 683-685.
53. Jonsson BA, Adami HO, Hagglund M, Bergh A, Goransson I, Stattin P, Wiklund F, Gronberg H: -160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer. Int J Cancer,2004.109(3): 348-352.
54. Gsur A, Feik E, Madersbacher S: Genetic polymorphisms and prostate cancer risk. World J Urol,2004.21(6): 414-423.
55. Tsukino H, Kuroda Y, Imai H, Nakao H, Qiu D, Komiya Y, Inatomi H, Hamasaki T, Kohshi K, Osada Y, Katoh T: Lack of evidence for the association of E-cadherin gene polymorphism with increased risk or progression of prostate cancer. Urol Int,2004.72(3): 203-207.
56. Gsur A, Preyer M, Haidinger G, Zidek T, Madersbacher S, Schatzl G, Marberger M, Vutuc C, Micksche M: Polymorphic CAG repeats in the androgen receptor gene, prostate-specific antigen polymorphism and prostate cancer risk. Carcinogenesis,2002.23(10): 1647-1651.
57. Irvine RA, Yu MC, Ross RK, Coetzee GA: The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res,1995.55(9): 1937-1940.
58. Lunn RM, Bell DA, Mohler JL, Taylor JA: Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2).
Carcinogenesis,1999.20(9): 1727-1731.
59. Xue W, Irvine RA, Yu MC, Ross RK, Coetzee GA, Ingles SA: Susceptibility to prostate cancer: interaction between genotypes at the androgen receptor
and prostate-specific antigen loci. Cancer Res,2000.60(4): 839-841.
60. Moody DB, Robinson JC, Ewing CM, Lazenby AJ, Isaac WB: Interleukin-2 transfected prostate cancer cells generate a local antitumor effect in vivo.
Prostate,1994.24(5): 244-251.
61. Hrouda D, Dalgleish AG: Gene therapy for prostate cancer. Gene Ther,1996.
3(10): 845-852.
62. Belldegrun A, Tso CL, Zisman A, Naitoh J, Said J, Pantuck AJ, Hinkel A, deKernion J, Figlin R: Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum Gene Ther,2001.12(8): 883-892.
63. Triest JA, Grignon DJ, Cher ML, Kocheril SV, Montecillo EJ, Talati B, Tekyi-Mensah S, Pontes JE, Hillman GG: Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model. Clin Cancer Res,1998.4(8):
2009-2014.
64. Hautmann SH, Huland E, Huland H: Local intratumor immunotherapy of prostate cancer with interleukin-2 reduces tumor growth. Anticancer Res,1999. 19(4A): 2661-2663.
65. Lloyd SN, McClinton S, brown IL, Miller ID, Kirk D, Eremin D, Moffat LE, Leake RE: Epidermal growth factor receptor, nuclear proliferation antigen and interleukin-2 receptor expression in prostatic cancer. J Clin Lab Immunol,1990. 32(2): 55-58.
66. Savage SA , Abnet CC , Haque K, Mark SD, Qiao YL, Dong ZW, Dawsey SM, Taylor PR , Chanock SJ: Polymorphisms in interleukin-2,-6,and-10 are not associated with gastric cardia or esophageal cancer in a high risk Chinese population. Cancer Epidemiol Biomarkers Prev, 2004.13: 1547-1549.
67. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB, Line SR, Sergio R P: Investigation of an IL-2 ploymorphism in patients with different levels of chronic periodontitis. J Clini Periodontol,2002.29(7): 287-91.
表與圖
Table 1. CDH-1 基因 3’-UTR C/T、IL-2 基因 exon 1, position +114 G/T 和 IL-2Rβ 基因 C/T 進行 RFLP 的反應條件
基因名稱 引子 片段大小 Annealing 溫度 限制酶 限制酶作用溫度
5’-CAGACAAAGACCAGGACTAT-3’ 172 bp T CDH-1
3’-UTR C/T 5’-AAGGGAGCTGAAAAACCACCAGCCAC-3’ 146+26 bp C 56℃ Pml I 37℃
5’-TGGGAAGCACTTAATTATCA-3’ 262 bp T IL-2 G/T
(AF228636) 5’-TAACCTCAACTCCTGCCACA-3’ 151+111 bp G 57℃ Mwo I 60℃
5’-AAGGACACCATTCCGTGGCT-3’ 101 bp T IL-2Rβ C/T
5’-CCGGTGTTCCTGCAGTTGAT-3’ 63+38 bp C 62 to 52℃
touch-down Hae III 37℃
Table 2. 前列腺病人與正常人 CDH-1、IL-2、IL-2Rβ 基因多型性基因型分佈的情
Table 3. 前列腺病人的年齡、臨床分級、病理分級和賀爾蒙治療反應與 CDH-1 C/T
基因型的分佈情形。
Genotype CC CT TT Total p value*
Grading 0.987
Well differentiated 15 13 0 28 Moderately differentiated 15 15 0 30 Poorly differentiated 19 18 1 38
Staging 0.065
Local 22 31 0 53 (0.289)
Advanced 13 7 0 20
Metastasis 14 8 1 23
Age 0.757
≦70 25 25 0 50
＞70 24 21 1 46
Responsiveness 0.474
Response 25 16 1 42
No response 5 7 0 12
* Fisher’s exact test
Table 4. 前列腺病人的年齡、臨床分級、病理分級和賀爾蒙治療反應與 IL-2 G/T
基因型的分佈情形。
Genotype CC CT TT Total p value*
Grading 0.936
Well differentiated 11 12 6 29 Moderately differentiated 9 15 6 30 Poorly differentiated 11 17 9 37
Staging 0.552
Local 20 24 9 53
Advanced 6 8 6 20
Metastasis 5 12 6 23
Age 0.55
≦70 13 22 12 50
＞70 18 22 9 46
Responsiveness 0.36
Response 9 22 11 42
No response 5 5 2 12
* Fisher’s exact test
Figure 1. CDH-1 3’-UTR C/T 定序的結果。(a)箭頭的位置表示並序的結果為 C/T (b)
箭頭的位置表示並序的結果為C (c)箭頭的位置表示並序的結果為 T
Figure 2. CDH-1 3’-UTR C/T 基因經 PCR 放大後的片段利用限制酶 Pml I 作用後
所得的電泳圖。
Figure 3. IL-2 T/G 基因經 PCR 放大後的片段利用限制酶 Mwo I 作用後所得的電
泳圖。
Figure 4. IL-2Rβ C/T 基因經 PCR 放大後的片段利用限制酶 Hae III 作用後所得的
電泳圖。
Figure 5. 利用 Kapalan-Meier 存活曲線分析前列腺癌病人的存活率與 IL-2（figure
1a, Log rank test, p=0.310）、IL-2Rβ（figure 1b, Log rank test, p=0.915）基因多型
性的關係。
a.
b.