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研究生:馮佩棻
研究生(外文):Pei-Fen Fong
論文名稱:探討介白質-六造成大腸直腸癌細胞第三號誘捕受體表現增加之訊息傳遞
論文名稱(外文):Elucidation of Signaling Pathways Involving in Interleukin-6 (IL-6) Induced Decoy Receptor 3 (DcR3) Expression in a Colorectal Cancer Cell Line
指導教授:陳紀如陳紀如
指導教授(外文):Chi-Ju ChenChi-Ju Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
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:45
中文關鍵詞:介白質-六第三號誘餌受體
外文關鍵詞:DcR3IL-6decoy receptor 3interleukin-6
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人類第三號誘餌受體 (decoy receptor 3,DcR3) 屬於腫瘤壞死因子受體家族(TNFR, tumor necrosis factor receptor super family)中的一員。由於DcR3缺乏穿膜區域 (transmembrane domain),並且會分泌到細胞外,因此DcR3會阻斷與其結合的腫瘤壞死因子原本應傳遞細胞凋零 (apoptosis) 訊息。此外也發現DcR3可以直接作用在許多免疫細胞上,改變其訊息傳遞路徑,調節免疫系統走向TH2的形態,而有利於癌症發展。在許多癌症及自體免疫疾病都發現到DcR3的大量表現,其中大腸癌DcR3表現極為顯著。研究發現以格蘭式陰性細菌細胞壁的脂多糖 (lipopolysaccharide, LPS) 刺激大腸癌細胞株可造成DcR3大量表現,代表細胞在接受感染時發炎放出的細胞激素 (cytokine) 可能調控DcR3表現,而介白質-六 (IL-6)即是一個被發現在大腸癌大量常產生的一個細胞激素。我們證實IL-6可增加大腸癌細胞SW480的DcR3表現。進一步探討IL-6下游的訊息傳遞,我們發現JAK-STAT的訊息調控內生性DcR3表現,也對IL-6誘發DcR3表現的機制十分重要,而下游影響DcR3的轉錄因子是STAT3。另一方面,由於SW480本身即帶有致癌基因ras的突變,所以我們的系統僅能證明ras下游的ERK的訊息對於內生性DcR3重要,無法得知IL-6是否會透過活化ERK訊息而增加DcR3表現。 最後我們也發現卡波西式肉瘤相關病毒 (KSHV) 在病毒溶解期 (lytic stage)產生的vIL-6,同樣也可以如同人類IL-6一般增加DcR3表現。以上結果證實了在大腸癌的微環境裡,IL-6是增加DcR3大量表現的因子。未來我們可以進一步探求其餘IL-6大量表現的癌症裡,是否也伴隨DcR3的表現量上升,針對IL-6與受體結合的模式或是下游訊息傳遞,設計出阻斷DcR3表現的療法,而幫助相關癌症的治療與預後。
Decoy Receptor 3 (DcR3) is a secretory TNFR (tumor necrosis factor receptor) overexpressed in many types of tumors. DcR3 can block the apoptosis signals transmitted by its ligands and also can shift immune system to TH2 type. Thus, tumors express DcR3 can get more advantages to fight with host immune system. Interleukin-6 (IL-6) is a proinflammatory cytokine highly express in colon cancer, where DcR3 is also overexpressed. We found IL-6 can upregulate DcR3 transcription and protein expression up to 2-fold. Among signals transduced by IL-6, JAK-STAT is important for both endogenous and IL-6 induced DcR3 expression. By knocking down STAT1 and STAT3 respectively with siRNA, we confirmed STAT3 is the key transcription factor for IL-6 induced DcR3 expression. Meanwhile, we failed to confirm if ERK signaling is also important for IL-6 induced DcR3 expression because the cell line that we use carries ras mutation, which is upstream of ERK signaling. We also found the viral IL-6 (vIL-6) expressed during KSHV lytic cycle, can also induce DcR3 expression. These results suggest that IL-6 is responsible for higher DcR3 expression in colon cancer and acutely inflamed intestinal epithelia.
摘要……………………………………………………....2
Abstract………………………………………………….3
緒論……………………………………………………....4
動機………………………………………………………9
材料與方法……………………………………………..10
結果……………………………………………………..20
結論……………………………………………………..27
討論……………………………………………………..28
圖表……………………………………………………..31
參考資料………………………………………………..40
附錄……………………………………………………..44
1. Aaronson, D. S., and C. M. Horvath. 2002. A road map for those who don't know JAK-STAT. Science 296:1653-5.
2. Akira, S. 2000. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19:2607-11.
3. Aoki, Y., M. Narazaki, T. Kishimoto, and G. Tosato. 2001. Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpesvirus. Blood 98:3042-9.
4. Ashizawa, T., R. Okada, Y. Suzuki, M. Takagi, T. Yamazaki, T. Sumi, and T. Aoki. 2006. Study of interleukin-6 in the spread of colorectal cancer: the diagnostic significance of IL-6. Acta Med Okayama 60:325-30.
5. Bai, C., B. Connolly, M. L. Metzker, C. A. Hilliard, X. Liu, V. Sandig, A. Soderman, S. M. Galloway, Q. Liu, C. P. Austin, and C. T. Caskey. 2000. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci U S A 97:1230-5.
6. Bamias, G., S. I. Siakavellas, K. S. Stamatelopoulos, E. Chryssochoou, C. Papamichael, and P. P. Sfikakis. 2008. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clin Immunol 129:249-55.
7. Becker, C., M. C. Fantini, C. Schramm, H. A. Lehr, S. Wirtz, A. Nikolaev, J. Burg, S. Strand, R. Kiesslich, S. Huber, H. Ito, N. Nishimoto, K. Yoshizaki, T. Kishimoto, P. R. Galle, M. Blessing, S. Rose-John, and M. F. Neurath. 2004. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21:491-501.
8. Becker, C., M. C. Fantini, S. Wirtz, A. Nikolaev, H. A. Lehr, P. R. Galle, S. Rose-John, and M. F. Neurath. 2005. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 4:217-20.
9. Chang, Y. C., Y. H. Chan, D. G. Jackson, and S. L. Hsieh. 2006. The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion. J Immunol 176:173-80.
10. Chang, Y. C., T. C. Chen, C. T. Lee, C. Y. Yang, H. W. Wang, C. C. Wang, and S. L. Hsieh. 2008. Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood 111:5054-63.
11. Chang, Y. C., T. L. Hsu, H. H. Lin, C. C. Chio, A. W. Chiu, N. J. Chen, C. H. Lin, and S. L. Hsieh. 2004. Modulation of macrophage differentiation and activation by decoy receptor 3. J Leukoc Biol 75:486-94.
12. Connor, J. P., and M. Felder. 2008. Ascites from epithelial ovarian cancer contain high levels of functional decoy receptor 3 (DcR3) and is associated with platinum resistance. Gynecol Oncol 111:330-5.
13. Coussens, L. M., and Z. Werb. 2002. Inflammation and cancer. Nature 420:860-7.
14. Decker, T., and P. Kovarik. 2000. Serine phosphorylation of STATs. Oncogene 19:2628-37.
15. Esfandi, F., S. Mohammadzadeh Ghobadloo, and G. Basati. 2006. Interleukin-6 level in patients with colorectal cancer. Cancer Lett 244:76-8.
16. Farley, S. M., D. E. Purdy, O. P. Ryabinina, P. Schneider, B. E. Magun, and M. S. Iordanov. 2008. Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases. J Biol Chem 283:919-28.
17. Fujita, J., O. Yoshida, Y. Ebi, H. Nakayama, H. Onoue, J. S. Rhim, and Y. Kitamura. 1988. Detection of ras oncogenes by analysis of p21 proteins in human tumor cell lines. Urol Res 16:415-8.
18. Galizia, G., M. Orditura, C. Romano, E. Lieto, P. Castellano, L. Pelosio, V. Imperatore, G. Catalano, C. Pignatelli, and F. De Vita. 2002. Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol 102:169-78.
19. Gill, R. M., and J. S. Hunt. 2004. Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis. Am J Pathol 165:309-17.
20. Grau, A. M., P. K. Datta, J. Zi, S. K. Halder, and R. D. Beauchamp. 2006. Role of Smad proteins in the regulation of NF-kappaB by TGF-beta in colon cancer cells. Cell Signal 18:1041-50.
21. Han, B., R. Bojalil, L. M. Amezcua-Guerra, R. Springall, H. Valderrama-Carvajal, J. Wu, and H. Luo. 2008. DcR3 as a diagnostic parameter and risk factor for systemic lupus erythematosus. Int Immunol 20:1067-75.
22. Heinrich, P. C., I. Behrmann, G. Muller-Newen, F. Schaper, and L. Graeve. 1998. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334 ( Pt 2):297-314.
23. Herbeuval, J. P., E. Lelievre, C. Lambert, M. Dy, and C. Genin. 2004. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol 172:4630-6.
24. Hodge, D. R., E. M. Hurt, and W. L. Farrar. 2005. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502-12.
25. Hoischen, S. H., P. Vollmer, P. Marz, S. Ozbek, K. S. Gotze, C. Peschel, T. Jostock, T. Geib, J. Mullberg, S. Mechtersheimer, M. Fischer, J. Grotzinger, P. R. Galle, and S. Rose-John. 2000. Human herpes virus 8 interleukin-6 homologue triggers gp130 on neuronal and hematopoietic cells. Eur J Biochem 267:3604-12.
26. Hsu, T. L., Y. C. Chang, S. J. Chen, Y. J. Liu, A. W. Chiu, C. C. Chio, L. Chen, and S. L. Hsieh. 2002. Modulation of dendritic cell differentiation and maturation by decoy receptor 3. J Immunol 168:4846-53.
27. Hsu, T. L., Y. Y. Wu, Y. C. Chang, C. Y. Yang, M. Z. Lai, W. B. Su, and S. L. Hsieh. 2005. Attenuation of Th1 response in decoy receptor 3 transgenic mice. J Immunol 175:5135-45.
28. Ivashkiv, L. B., and X. Hu. 2004. Signaling by STATs. Arthritis Res Ther 6:159-68.
29. Kamimura, D., K. Ishihara, and T. Hirano. 2003. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1-38.
30. Kim, S., A. Fotiadu, and V. Kotoula. 2005. Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Clin Immunol 115:286-94.
31. Kim, S., W. J. McAuliffe, L. S. Zaritskaya, P. A. Moore, L. Zhang, and B. Nardelli. 2004. Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells. Infect Immun 72:89-93.
32. Kojima, H., K. Nakajima, and T. Hirano. 1996. IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s). Oncogene 12:547-54.
33. Konnikova, L., M. Kotecki, M. M. Kruger, and B. H. Cochran. 2003. Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23.
34. Korchynskyi, O., M. Landstrom, R. Stoika, K. Funa, C. H. Heldin, P. ten Dijke, and S. Souchelnytskyi. 1999. Expression of Smad proteins in human colorectal cancer. Int J Cancer 82:197-202.
35. Levy, D. E., and J. E. Darnell, Jr. 2002. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651-62.
36. Li, H., H. Wang, and J. Nicholas. 2001. Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling. J Virol 75:3325-34.
37. Liu, X. Q., A. D. Paterson, N. He, P. St George-Hyslop, V. Rauta, C. Gronhagen-Riska, M. Laakso, L. Thibaudin, F. Berthoux, D. Cattran, and Y. Pei. 2008. IL5RA and TNFRSF6B gene variants are associated with sporadic IgA nephropathy. J Am Soc Nephrol 19:1025-33.
38. Luo, J. L., S. Maeda, L. C. Hsu, H. Yagita, and M. Karin. 2004. Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297-305.
39. Matsushita, M., K. Matsuzaki, M. Date, T. Watanabe, K. Shibano, T. Nakagawa, S. Yanagitani, Y. Amoh, H. Takemoto, N. Ogata, C. Yamamoto, Y. Kubota, T. Seki, H. Inokuchi, M. Nishizawa, H. Takada, T. Sawamura, A. Okamura, and K. Inoue. 1999. Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development. Br J Cancer 80:194-205.
40. McCoy, M. S., C. I. Bargmann, and R. A. Weinberg. 1984. Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene. Mol Cell Biol 4:1577-82.
41. McCoy, M. S., J. J. Toole, J. M. Cunningham, E. H. Chang, D. R. Lowy, and R. A. Weinberg. 1983. Characterization of a human colon/lung carcinoma oncogene. Nature 302:79-81.
42. McDermott, U., D. B. Longley, L. Galligan, W. Allen, T. Wilson, and P. G. Johnston. 2005. Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer. Cancer Res 65:8951-60.
43. Migone, T. S., J. Zhang, X. Luo, L. Zhuang, C. Chen, B. Hu, J. S. Hong, J. W. Perry, S. F. Chen, J. X. Zhou, Y. H. Cho, S. Ullrich, P. Kanakaraj, J. Carrell, E. Boyd, H. S. Olsen, G. Hu, L. Pukac, D. Liu, J. Ni, S. Kim, R. Gentz, P. Feng, P. A. Moore, S. M. Ruben, and P. Wei. 2002. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16:479-92.
44. Morris, T. L., R. R. Arnold, and J. Webster-Cyriaque. 2007. Signaling cascades triggered by bacterial metabolic end products during reactivation of Kaposi's sarcoma-associated herpesvirus. J Virol 81:6032-42.
45. Nakajima, K., Y. Yamanaka, K. Nakae, H. Kojima, M. Ichiba, N. Kiuchi, T. Kitaoka, T. Fukada, M. Hibi, and T. Hirano. 1996. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J 15:3651-8.
46. Ohshima, K., S. Haraoka, M. Sugihara, J. Suzumiya, C. Kawasaki, M. Kanda, and M. Kikuchi. 2000. Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. Cancer Lett 160:89-97.
47. Otsuki, T., A. Tomokuni, H. Sakaguchi, T. Aikoh, T. Matsuki, Y. Isozaki, F. Hyodoh, H. Ueki, M. Kusaka, S. Kita, and A. Ueki. 2000. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin Exp Immunol 119:323-7.
48. Pitti, R. M., S. A. Marsters, D. A. Lawrence, M. Roy, F. C. Kischkel, P. Dowd, A. Huang, C. J. Donahue, S. W. Sherwood, D. T. Baldwin, P. J. Godowski, W. I. Wood, A. L. Gurney, K. J. Hillan, R. L. Cohen, A. D. Goddard, D. Botstein, and A. Ashkenazi. 1998. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396:699-703.
49. Roth, W., S. Isenmann, M. Nakamura, M. Platten, W. Wick, P. Kleihues, M. Bahr, H. Ohgaki, A. Ashkenazi, and M. Weller. 2001. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 61:2759-65.
50. Sekikawa, A., H. Fukui, S. Fujii, K. Ichikawa, S. Tomita, J. Imura, T. Chiba, and T. Fujimori. 2008. REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. Carcinogenesis 29:76-83.
51. Shen, H. W., S. L. Gao, Y. L. Wu, and S. Y. Peng. 2005. Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. World J Gastroenterol 11:5926-30.
52. Simon, I., Y. Liu, K. L. Krall, N. Urban, R. L. Wolfert, N. W. Kim, and M. W. McIntosh. 2007. Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Gynecol Oncol 106:112-8.
53. Wan, X., G. Shi, M. Semenuk, J. Zhang, and J. Wu. 2003. DcR3/TR6 modulates immune cell interactions. J Cell Biochem 89:603-12.
54. Waris, G., and A. Siddiqui. 2002. Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function. J Virol 76:2721-9.
55. Yang, C. R., S. L. Hsieh, F. M. Ho, and W. W. Lin. 2005. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J Immunol 174:1647-56.
56. Yu, K. Y., B. Kwon, J. Ni, Y. Zhai, R. Ebner, and B. S. Kwon. 1999. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 274:13733-6.
57. Zhang, J., T. W. Salcedo, X. Wan, S. Ullrich, B. Hu, T. Gregorio, P. Feng, S. Qi, H. Chen, Y. H. Cho, Y. Li, P. A. Moore, and J. Wu. 2001. Modulation of T-cell responses to alloantigens by TR6/DcR3. J Clin Invest 107:1459-68.
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