黏液纖維肉瘤在臨床如何侵犯正常細胞的分子關鍵，目前尚未明確。然而利用微陣列比較基因雜合技術(array CGH)尋求在十二例黏液纖維肉瘤及二株黏液纖維肉瘤細胞株分析與腫瘤相關基因中發現，於第7染色體上有基因拷貝數放大或擴增之變異範圍，其中位於7p36.1 的EZH2亦有擴增的情形。從即時定量聚合酶反應檢測88例黏液纖維肉瘤分析數據驗證，具EZH2基因放大者，佔了11例，相當於12.5%，此比例與組織學惡性度3級在非移轉存活率之關聯均呈現顯著性差異(P=0.0001)。藉由免疫化學染色分析，亦可見EZH2的蛋白質表現與FNLCC分級有顯著性相關 (P<0.001)。其中約有51%具有EZH2高表現且與不良預後存活率(P=0.0001)、疾病專一存活率 (P=0.0001)及總存活率 (P=0.0001)均有顯著性差異。在體外試驗，將黏液纖維肉瘤細胞株EZH2蛋白靜默後，細胞週期停滯於S/G2過渡時期和G2時期，EZH2蛋白靜默或3’-Dznep抑制劑進行處理後，相關聯的SUZ12及H3K27-Me3腫瘤抑制標記的表現亦同時減弱。3’-Dznep藥物使用於黏液纖維肉瘤細胞株中有降低細胞存活能力，此現象於正常皮質纖維組織母細胞株則不受到影響。
EZH2蛋白的過度表現可代表黏液纖維肉瘤侵犯能力，而EZH2基因的增幅並非主要的調控機制，僅維持SUZ12及H3K27-Me3腫瘤抑制標記的特性，藉由EZH2的表現，可突顯出3’-Dznep藥物在黏液纖維肉瘤細胞株是具潛力之標靶治療藥物，其抑制效果擴及到與EZH2相關聯的PRC2 蛋白複合物。

Myxofibrosarcoma (MFS) remains obscure in molecular determinants of clinical aggressiveness. To identify cancer-associated genes, Array comparative genomic hybridization (aCGH) was used to profile copy-number alterations of myxofibrosarcoma, focusing on chromosomes 7 where EZH2 (7p36.1) is located.
EZH2 gene amplification was detected in 11 of 88 (12.5%) cases tested and correlated with grade 3 histology (p=0.001) and worse metastasis-free survival (p=0.0074). Immunohistochemically, EZH2 protein showed a stepwise increasing expression with the increment of FNLCC grades (p<0.001). Additionally, EZH2 overexpression was present in 51% of cases and strongly predictive of worse metastasis-free survival (p=0.001), disease-specific survival (p=0.001), and overall survival (p=0.0012). In vitro, EZH2 silencing resulted in cell cycle arrests at the S/G2 transition and G2 phase, while decreased SUZ12 and H3K27-Me3 repressive mark could be achieved by EZH2 silencing. 3’ Dnezp(3’-deaznaepolanocin A) decreased cell viability in myxofibrosarcoma cells but dermal fibroblasts were not responsive. In conclusion, EZH2 overexpression is representative of tumor aggressiveness of myxofibrosarcoma, while amplification appears not a predominant driving mechanism. Its expression contributes to maintaining SUZ12 expression and H3K27- Me3 repressive mark. EZH2 may emerge as a potential therapeutic target as 3’ Dnezp (3’-deaznaepolanocin A) can inhibit myxofibrosarcoma cells through targeting EZH2-asscoiated PRC2 complex.

論文審定書 …………………………………………………… i
中文摘要 ……………………………………………….….. ii
英文摘要 ……………………………………..……………. iii
前言 …………………………………………………… 1
材料與方法 …………………………………………………… 4
結果與討論 …………………………………………………… 13
結 論 …………………………………………………… 17
參考文獻 …………………………………………………… 18
圖表 …………………………………………………… 22

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衛生福利部國民健康署，101年癌症登記報告，中華民國104年2月出版