請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/43848
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭明良(Min-Liang Kuo) | |
dc.contributor.author | Chia-Chun Chi | en |
dc.contributor.author | 紀佳君 | zh_TW |
dc.date.accessioned | 2021-06-15T02:30:27Z | - |
dc.date.available | 2014-09-15 | |
dc.date.copyright | 2009-09-15 | |
dc.date.issued | 2009 | |
dc.date.submitted | 2009-08-16 | |
dc.identifier.citation | Auersperg N, Pan J, Grove BD, Peterson T, Fisher J, Maines-Bandiera S et al (1999). E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A 96: 6249-54.
Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC (2001). Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22: 255-88. Barton CA, Clark SJ, Hacker NF, O'Brien PM (2008). Epigenetic markers of ovarian cancer. Adv Exp Med Biol 622: 35-51. Belinsky SA, Klinge DM, Dekker JD, Smith MW, Bocklage TJ, Gilliland FD (2005). Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res 11: 6505-11. Berger SL (2007). The complex language of chromatin regulation during transcription. Nature 447: 407-12. Bernstein BE, Meissner A, Lander ES (2007). The mammalian epigenome. Cell 128: 669-81. Bojesen SE, Kjaer SK, Hogdall EV, Thomsen BL, Hogdall CK, Blaakaer J (2005). Increased risk of ovarian cancer in integrin beta3 Leu33Pro homozygotes. Endocr Relat Cancer 12: 945-52. Bowman RV, Yang IA, Semmler AB, Fong KM (2006). Epigenetics of lung cancer. Respirology 11: 355-65. Brown SE, Campbell RD, Sanderson CM (2001). Novel NG36/G9a gene products encoded within the human and mouse MHC class III regions. Mamm Genome 12: 916-24. Bryant RJ, Cross NA, Eaton CL, Hamdy FC, Cunliffe VT (2007). EZH2 promotes proliferation and invasiveness of prostate cancer cells. Prostate 67: 547-56. Cannistra SA (2004). Cancer of the ovary. N Engl J Med 351: 2519-29. Chen H, Yan Y, Davidson TL, Shinkai Y, Costa M (2006). Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Res 66: 9009-16. Chen J, Zhang J, Zhao Y, Li J, Fu M (2009). Integrin beta3 down-regulates invasive features of ovarian cancer cells in SKOV3 cell subclones. J Cancer Res Clin Oncol 135: 909-17. Cruet-Hennequart S, Maubant S, Luis J, Gauduchon P, Staedel C, Dedhar S (2003). alpha(v) integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells. Oncogene 22: 1688-702. Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feldmann G, Madelenat P (1997). Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. Hum Pathol 28: 922-8. Egger G, Liang G, Aparicio A, Jones PA (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature 429: 457-63. Esteller M (2007). Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286-98. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E (2000). Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92: 564-9. Feinberg AP, Tycko B (2004). The history of cancer epigenetics. Nat Rev Cancer 4: 143-53. Feinberg AP, Vogelstein B (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301: 89-92. Gillan L, Matei D, Fishman DA, Gerbin CS, Karlan BY, Chang DD (2002). Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility. Cancer Res 62: 5358-64. Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B (1989). Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 83: 155-8. Herman JG, Baylin SB (2003). Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: 2042-54. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S (1994). Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91: 9700-4. Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE (1995). Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525-30. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T et al (2003). Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163: 1437-47. Jenuwein T, Allis CD (2001). Translating the histone code. Science 293: 1074-80. Jenuwein T, Laible G, Dorn R, Reuter G (1998). SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell Mol Life Sci 54: 80-93. Kaneda A, Feinberg AP (2005). Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res 65: 11236-40. Karpf AR, Matsui S (2005). Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res 65: 8635-9. Kee SH, Steinert PM (2001). Microtubule disruption in keratinocytes induces cell-cell adhesion through activation of endogenous E-cadherin. Mol Biol Cell 12: 1983-93. Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E (2006). Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 38: 149-53. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA (2003). EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100: 11606-11. Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y, Haddad BR (2008). Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One 3: e2037. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y (2007). Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res 37: 974-83. Kouzarides T (2007). Chromatin modifications and their function. Cell 128: 693-705. Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML (2007). Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25: 473-81. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997). Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389: 251-60. Mack GS (2006). Epigenetic cancer therapy makes headway. J Natl Cancer Inst 98: 1443-4. Melki JR, Vincent PC, Clark SJ (1999). Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 59: 3730-40. Naora H, Montell DJ (2005). Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer 5: 355-66. Peters AH, O'Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C (2001). Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107: 323-37. Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R (2001). The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J 20: 7137-48. Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M (2008). Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res 68: 2329-39. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ, 3rd (2002). SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 16: 919-32. Schwartz AM, Man YG, Rezaei MK, Simmens SJ, Berg PE (2009). BP1, a homeoprotein, is significantly expressed in prostate adenocarcinoma and is concordant with prostatic intraepithelial neoplasia. Mod Pathol 22: 1-6. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M (2005). Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435: 1262-6. Shepherd TG, Theriault BL, Campbell EJ, Nachtigal MW (2006). Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients. Nat Protoc 1: 2643-9. Stack MS, Ellerbroek SM, Fishman DA (1998). The role of proteolytic enzymes in the pathology of epithelial ovarian carcinoma. Int J Oncol 12: 569-76. Strahl BD, Allis CD (2000). The language of covalent histone modifications. Nature 403: 41-5. Strobel T, Cannistra SA (1999). Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro. Gynecol Oncol 73: 362-7. Tachibana M, Sugimoto K, Fukushima T, Shinkai Y (2001). Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem 276: 25309-17. Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M (2002). G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16: 1779-91. Takeichi M (1995). Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7: 619-27. Tan DS, Agarwal R, Kaye SB (2006). Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol 7: 925-34. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG et al (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419: 624-9. Wozniak RJ, Klimecki WT, Lau SS, Feinstein Y, Futscher BW (2007). 5-Aza-2'-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 26: 77-90. Zhang X, Yang Z, Khan SI, Horton JR, Tamaru H, Selker EU (2003). Structural basis for the product specificity of histone lysine methyltransferases. Mol Cell 12: 177-85. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/43848 | - |
dc.description.abstract | G9a為哺乳動物的組蛋白甲基轉移酶,負責催化組蛋白H3上第九個離胺酸 (K9) 的甲基化,組蛋白H3K9的甲基化對腫瘤抑制基因 (tumor suppressor gene) 轉錄的抑制扮演關鍵性的角色。已知在缺氧的情形下,會誘發G9a表現及增加其甲基轉移酶活性進而調控基因表現。在乳癌細胞中,G9a也被發現可降低腫瘤抑制基因的表現,除此之外目前對於G9a在癌症上扮演的角色仍不甚清楚。先前本實驗室研究發現 G9a高度表現在不同類型癌症病人的腫瘤組織中,其中包括卵巢癌。大部份被診斷出患卵巢癌的病人皆已有腹腔轉移 (peritoneal metastasis) 的情形,因此,我們企圖探討G9a在卵巢癌症發展過程中的重要性及其調控機轉。
本篇研究結果顯示,臨床上分析74位卵巢癌病人有58位會表現G9a,並且G9a蛋白表現量較高的病人,與晚期卵巢癌,有腹腔轉移,及較短存活時間有正相關,在統計上也有顯著的意義(p<0.05)。在體外細胞株實驗中,相對於正常卵巢上皮細胞,不同卵巢癌細胞株高度表現G9a,而剔除G9a高表現卵巢癌細胞株中的G9a,可以抑制卵巢癌細胞之黏附和轉移浸襲能力。利用特異性G9a抑制劑阻斷G9a的組蛋白甲基轉移活性,可以抑制卵巢癌細胞的浸襲能力,顯示G9a的酵素活性參與在G9a調控卵巢癌轉移的轉移浸襲能力中。另外,我們發現在剔除G9a表現的卵巢癌細胞株中,同時會增加E-cadherin的表現量。我們進一步研究E-cadherin是否參與在G9a所調控之卵巢癌細胞浸襲能力中,實驗結果顯示,當剔除E-cadherin表現,可以回復剔除G9a所抑制之卵巢癌細胞浸襲能力。此外動物實驗結果顯示,剔除G9a可以抑制癌細胞在腹腔中的散佈及浸襲。綜合以上實驗結果,顯示G9a在卵巢癌發生過中扮演重要的調控角色,並且未來有機會運用在腫瘤轉移之臨床檢測與治療上。 | zh_TW |
dc.description.abstract | G9a is a mammalian histone methyltransferase and catalyzes the histone 3 lyine 9 dimethylation, which was known to involve in the epigenetic silencing of tumor suppressor genes. However, the role of G9a on tumor progression remains widely unknown. Our previous studies, G9a predominately expressed in the tumor parts of different cancer types, including ovarian cancer. Hence, the goal of this study was to elucidate the role of G9a in ovarian cancer progression.
In our present studies, G9a expression was not only found in 58 of 74 ovarian cancer patients (78 %) but also be statistically significantly associated with patients had advanced stage disease (p < 0.01) and peritoneal metastasis (p < 0.05), respectively. In addition, G9a overexpressed in ovarian cancer cells comparing to normal epithelial surface ovarian cells (OSEs). Ovarian cancer cell line highly expressing G9a, SKOV-3 and ES-2, were infected with G9a-shRNA expressing lentivirus significantly inhibit the adhesion, wound-healing migration, invasion abilities of cells. By G9a specific inhibitor, BIX01294, blockage of G9a methyltransferase activity also inhibited cell invasion ability. The expression of mRNA and protein of E-cadherin were up-regulated in G9a knockdown SKOV-3 and ES-2 cells. Treatment with E-cadherin shRNA restored the invasion ability of stable G9a knockdown cells. Moreover, in vivo animal model showed that G9a knockdown suppressed tumor peritoneal dissemination and invasion. In conclusion, our data suggest that G9a promotes peritoneal metastasis of ovarian cancer. Targeting G9a could be a therapy for ovarian cancer patient. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T02:30:27Z (GMT). No. of bitstreams: 1 ntu-98-R96447011-1.pdf: 5375330 bytes, checksum: 95b20a2bb97a4c6d908f796b81b1dc04 (MD5) Previous issue date: 2009 | en |
dc.description.tableofcontents | 中文摘要...................................................4
Abstract...................................................5 Introduction...............................................6 Materials and Methods.....................................11 Results...................................................18 G9a expressed in advanced stage tumors and correlated with poor prognosis............................................18 G9a expression induced adhesion, migratory and invasive phenotype in ovarian cancer cells.........................19 G9a knockdown inhibits peritoneal metastasis in vivo......22 E-cadherin acted as an effector in G9a-induced invasive phenotype.................................................23 Discussion................................................25 Reference.................................................30 Figures and figure legends................................36 Tables....................................................54 | |
dc.language.iso | en | |
dc.title | 組蛋白甲基轉移酶G9a在卵巢癌腹膜腔轉移及浸襲之角色評估 | zh_TW |
dc.title | Evaluation of the role of histone methyltransferase G9a in peritoneal dissemination and invasion of ovarian cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 97-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蕭宏昇(Michael Hsiao),夏興國(Shiah-shine Gwo),嚴孟祿(Men-Luh Yen) | |
dc.subject.keyword | 卵巢癌,組蛋白甲基轉移酶,腹腔轉移,浸襲能力,黏附能力, | zh_TW |
dc.subject.keyword | ovarian cacner,peritoneal metastasis,G9a,e-cadherin, | en |
dc.relation.page | 54 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2009-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-98-1.pdf 目前未授權公開取用 | 5.25 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。