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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 Evaluation of the role of histone methyltransferase G9a in peritoneal dissemination and invasion of ovarian cancer |
Authors: | Chia-Chun Chi 紀佳君 |
Advisor: | 郭明良(Min-Liang Kuo) |
Keyword: | 卵巢癌,組蛋白甲基轉移酶,腹腔轉移,浸襲能力,黏附能力, ovarian cacner,peritoneal metastasis,G9a,e-cadherin, |
Publication Year : | 2009 |
Degree: | 碩士 |
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。 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. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/43848 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 毒理學研究所 |
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