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研究生:陳泓志
研究生(外文):Hung-chih Chen
論文名稱:探討甲基胞嘧啶、羥甲基胞嘧啶與表觀遺傳修飾者的表現量與舌部鱗狀細胞癌的發展及預後之關聯性
論文名稱(外文):The Association of 5-methylation, 5-hydroxymethylation and Epigenetic Modifiers’ Expression with the Development and Prognosis of Tongue Squamous Cell Carcinoma
指導教授:葛魯蘋葛魯蘋引用關係陳錦翠
指導教授(外文):Luo-Ping GerJiin-Tsuey Chen
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:104
中文關鍵詞:十十一易位蛋白5-羥甲基胞嘧啶組織微陣列晶片異檸檬酸脫氫酶5 -甲基胞嘧啶舌部鱗狀細胞癌存活免疫組織化學分析
外文關鍵詞:5hmcTETtissue microarrayIDHtongue squamous cell carcinomaimmunohistochemistry5mcsurvival
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  背景: 口腔癌在台灣為男性癌症死亡率第四名並且是台灣年輕男性中最常見的癌症之一。舌部鱗狀細胞癌是頭頸部的口腔惡性腫瘤最常見的部位之一,且一般預後較差。5 -甲基胞嘧啶(5mc)是癌症發生常見的表觀遺傳特徵。5-羥甲基胞嘧啶(5hmc)是5mc去甲基化過程的中間產物,在多種癌症中(包括口腔癌)中也有下降的趨勢。最近的證據表明TET蛋白(十十一易位蛋白)依賴α-酮戊二酸的氧化反應可以進一步催化5mc轉變成為5hmC。此外,IDH蛋白(異檸檬酸脫氫酶)可以催化異檸檬酸鹽轉換成為α-酮戊二酸,而α-酮戊二酸是催化5mc轉變成5hmc重要的輔助因子。
 
  方法: 本研究的目的是利用免疫組織化學法,染色在組織微陣列晶片上248例手術切除之舌癌組織與癌旁正常黏膜組織,分析5mc、5hmc、TET1(N)、TET1(C)、TET2(N)、TET2(C)、IDH1、IDH2的表現量與舌癌患者的疾病發生和存活的關係。
 
  結果: 結果發現5mc、5hmc、TET1(N)、TET2(N) 和IDH2蛋白在舌癌組織中的表現量與癌旁正常黏膜組織比較均顯著減少(p< 0.001),相反的,IDH1、TET1(C)、TET2(C)的表現量反而增加(p = 0.01,p <0.001,p = 0.036)。舌癌患者中女性比男性的5mc表現量較低,另外發現IDH1表現量的增加易發生於高分化程度的舌癌患者(p = 0.027)。舌癌患者的疾病特定存活曲線在廣泛性低度甲基化組顯著較低(p = 0.048),尤其是發生在性別為女性(p = 0 .028)、較小的腫瘤T1~T2 (P = 0.004)、無淋巴結轉移患者(P = 0.049) 和術後接受放射線治療的患者(P = 0.005)。此外,在女性患者中,凡5hmc (p = 0.015)和IDH1(p = 0.021)表現量高者,具顯著較低之復發率。最後,發現在女性(p = 0 .021)、病理分期晚期(Ⅲ〜Ⅳ期,p = 0 .047)或術後接受放射線治療患者(p = 0.025),具高表現量TET2(C)的患者呈現顯著較差的疾病特定存活曲線。
 
  結論: 5mc、5hmc、TET1、TET2、IDH1、IDH2可能是舌部鱗狀細胞癌發生之生物標誌。此外,5mc是舌部鱗狀細胞癌的獨立預後指標。
  Backgrounds: In Taiwan, oral cancer is the 4th leading cause of cancer death for males and the top common cancer in young adult males. Tongue squamous cell carcinoma (SCC) is one of the most common oral cancers and generally associated with poor prognosis. DNA methylation at the 5 position of cytosine (5mC) is a well-known epigenetic feature of cancer. In addition, 5-hydroxymethylcytosine (5hmc), an intermediator of gene demethylation, is reduced in cancer, including oral cancer. Recent evidences suggest that a group of enzymes of the ten-eleven translocation proteins (TET) can further convert 5mC to 5hmC in an α-ketoglutarate (α-KG) dependent oxidation reaction. In addition, isocitrate dehydrogenase (IDH) can catalyze the interconversion of isocitrate to α-KG, which is the cofactor to catalyze 5mC to 5hmC.
 
  Methods: The purpose of this study was to investigate the relationship of the levels of 5mc, 5hmc, TET1, TET2, IDH1 and IDH2 with the tumorigenesis and survival in 248 surgically resected tongue SCC tissues by immunohistochemistry using tissue microarray slides.
 
  Results: We found that expression levels of 5mc, 5hmc, TET1(N) , TET2(N) and IDH2 proteins in tongue SCC tissues were significantly reduced (all p < 0.001) as compared to the corresponding tumor adjacent normal tissues (CTAN), except for the increase of IDH1, TET1(C) , TET2(C) (p= 0.01, p < 0.001, p=0.036, respectively). Among tongue SCC tissues, decreased expression of 5mc was associated with female gender, and increased expression of IDH1 was associated with low-grade (well) differentiation (p= 0.027). In addition, the global hypomethylation was associated with the poor disease-specific survival in tongue SCC patients (p= 0.048), especially for patients in female gender (p =0 .028), with small tumor size (T1-T2, p=0.004), without nodal metastasis (N0, p =0 .049), and ever received post-operative radiotherapy (p=0.005). For female patients, those with high levels of 5hmc (p =0.015) and IDH1 expression (p =0 .021) had significantly better disease-free survival. Finally, high level of TET2(C) expression was correlated with the poor disease-specific survival for patients with female gender (p =0 .021), late pathologic stage (III-IV, p =0 .047), or ever received post-operative radiotherapy (p=0.025).
 
  Conclusions: 5mc, 5hmc, TET1, TET2, IDH1 and IDH2 may be biomarkers for development of tongue SCC. Additionally, 5mc might be the independent prognostic biomarkers for tongue SCC.
Abbreviations i
Abstract in Chinese ii
Abstract in English iii
Contents iv-v
Introduction
 1. Epidemiology of Tongue Squamous Cell Carcinoma 1-3
 2. 5-methylcytosine (5mC) 3
 3. Nonspecific (or global) DNA hypomethylation of cancer 4-5
 4. 5-hydroxymethylcytosine (5hmC) 5-6
 5. Ten-eleven translocation protein (TET) 6-8
 6. Isocitrate dehydrogenase protein (IDH) 9-10
Specific Aims 11
Materials and Methods 12-15
Results
 1. The demographic and clinicopathologic characteristics and their impact on survival of patients with tongue SCC 16-18
 2. The expression levels of 5mc, 5hmc, and Epigenetic Modifiers in normal tissue, tumor adjacent normal tissue and tumor tissue 18-20
 3. The association of the expression levels of 5mc with the clinicopathological outcomes and survival of patients with tongue SCC 21-22
 4. The association of the expression levels of 5hmc with the clinicopathological outcomes and survival of patients with tongue SCC 22-23
 5. The association of the expression levels of epigenetic modifiers with the clinicopathological outcomes and survival of patients with tongue SCC 23-24
 6. The association of the expression levels of 5hmc and epigenetic modifiers in tongue SCC 24-25
Discussion 26-39
Conclusion 40
References 41-57
Tables 58-67
Figures 68-94
Indexes 95-96
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