2012-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/686903摘要：第二型內膜癌佔所有內膜癌的10 %，但在所有子宮癌症中，有將近50 %的復發率。子宮乳頭狀漿液性癌，第二型內膜癌最常見的形式，是一種極具侵襲性的癌症，理想的處置方式仍在研究中。近來的研究顯示癌細胞的特色為非基因層次的調控出現問題，包含組蛋白的修飾作用。組蛋白胺基酸尾端的修飾會影響調控因子和核染質的組成，進而影響生物功能。在這些非基因層次的序列中的重要組成之一為組蛋白H3第九個離胺酸的甲基化，由組蛋白甲基轉移酶所執行並且經常伴演基因抑制的功能。然而，組蛋白H3第九個離胺酸甲基化轉移酶在第二型內膜癌的功能及它的下游調控基因仍尚未釐清。為了探討組蛋白H3第九個離胺酸甲基化轉移酶(G9a)在第二型內膜癌的角色，我們測試了G9a抑制劑對子宮乳頭狀漿液性癌的作用，發現G9a抑制劑可以顯著抑制子宮乳頭狀漿液性癌細胞株的增殖作用，特別是USPC-ARK1及USPC-ARK2這兩個細胞株，在G9a抑制劑1.25 M濃度作用下，幾乎可以被完全抑制，顯示G9a活性在子宮乳頭狀漿液性癌的增生過程中伴演重要角色。為了釐清G9a是否可以當成子宮乳頭狀漿液性癌的治療標的，我們提出此研究計畫在體外實驗及活體中進一步分析G9a在子宮乳頭狀漿液性癌的致病過程中的角色。<br> Abstract: Type 2 cancers represent 10% of all endometrial cancers but approximately 50% of alluterine cancer relapses. Uterine papillary serous cancer, the most common form of type IIendometrial cancer, is an extremely aggressive cancer, the optimum management of which isstill being determined. Recent advances have shown that cancer cells are characterized byprominent epigenetic dysregulation, including histone modifications. Modifications of thehistone amino-terminal tails affect access of regulatory factors and complexes to chromatinand thereby influence biological processes. An important component of this epigenetic codeis methylation of histone H3 at lysine 9 (H3K9me), which is catalyzed by histonemethyltransferases and generally leads to gene repression. However, the function and genetictargets of H3K9 methyltransferases in type II endometrial cancer remain unclear. To this end,we focus on histone modifications and the functional roles of the HMT in type IIendometrial cancers. We then therefore test whether inhibitions of G9a activity may result incellular senescence of UPSC, the specific G9a inhibitor BIX01294 were used. To oursurprise, we observed that BIX01294 treatment significant inhibits cell proliferation in allUPSC cell lines tested. In particular, BIX01294 at 1.25 M almost completely abolishedcellular growth of USPC-ARK1 and USPC-ARK2, indicating inhibition of G9a activityresulted in cellular senescence of UPSC. To verify G9a as a molecular therapeutic target forUPSC, we propose this project to further analyze the pathogenetic role of G9a in UPSC invitro and in vivo and to exam the possibility that whether the G9a may act as a therapeutictarget in type II endometrial cancers.