臺灣博碩士論文加值系統

肝癌業已成為台灣地區人民的頭號生命殺手，慢性B型肝炎與C型肝炎病毒感染為誘發肝癌發生的主要危險因子。近年許多研究指出，腫瘤抑制基因其基因調節區之甲基化可造成基因的表現異常，且與許多人類癌症的生成是息息相關的，肝癌亦是如此；第十六號染色體異質性消失現象常發生於肝癌檢體組織中，意味著有腫瘤抑制基因分布在此染色體上。本試驗之目的首先重於第十六號染色體上腫瘤抑制基因群TSC2、SOCS1、CDH1、E2F4與CDH13於肝癌基因體中甲基化程度之探討，初步試驗結果顯示，CDH13基因的甲基化比例最高(39.4%)，其次為SOSC1與CDH1基因(20.6%)，而TSC2與E2F4基因則無甲基化。本研究進一歩探討CDH13基因於肝癌中的mRNA與蛋白質表現情形，結果顯示甲基化之CDH13基因在肝腫瘤組織的mRNA表現皆高於正常肝臟組織；且於腫瘤切片的免疫組織化學分析中，顯示CDH13蛋白於肝實質部細胞與肝竇狀血管系統有大量的表現。在三個肝癌細胞株中，亦發現較高度甲基化的CDH13基因其mRNA表現量較高，且在細胞質與膜蛋白表現上，具高度CDH13基因甲基化之HA22T細胞株相較於基因未甲基化之細胞株(HepG2與Hep3B)明顯有不同之蛋白構型。最後，經由Bisulfite-定序分析與搜尋CDH13基因調節區上可能的轉錄作用因子結合位，顯示含CpG序列之特定轉錄作用因子可能受甲基化修飾作用而影響其對基因的調控能力。

In Taiwan, hepatocellular carcinoma is the leading cause of cancer death. Hepatitis B virus and hepatitis C virus infections are the major contributing factors of hepatocarcinogenesis. Recent studies have reported that aberrant hypermethylation in the CpG-rich promoter regions of many tumor suppressor genes is associated with the lack of gene transcription and the development of hepatocellular carcinoma. Loss of heterozygosity on chromosome 16 is a common genetic alternation in human hepatocarcinomas, indicating the existence of tumor suppressor genes on this chromosome. In this study, we focus on the gene mehtylation studies of hundreds hepatoma biopsies in five selected potential tumor suppressor genes, named TSC2, SOCS1, E2F4, CDH1 and CDH13 genes, which located on human chromosome 16. Aberrant methylation frequencies of this 5 genes detected by MS-PCR in 155 hepatoma pairs were39.4% for CDH13, 20.6% for SOCS1 and CDH1, 0% for TSC2 and E2F4. In mRNA expression assay, CDH13 gene hypermethylated hepatoma cells exhibited higher CDH13 mRNA level than its normal tissue pairs. This phenomenon has been demonstrated in three hepatoma cell lines that HA22T cell line with CDH13 gene hypermethylation obtained highest CDH13 mRNA expression, while HepG2 and Hep3B cell lines with CDH13 gene unmethylation showed no detectable CDH13 mRNA expression. In protein expression assay, CDH13 proteins appeared three different isoforms located on cytosol and membrane and differential display in three hepatoma cell lines. In CDH13 protein immunohistochemistry staining, overexpressed CDH13 protein has been detected in tumor vessels and hepatocytes in different hepatitis viruses-infected hepatoma cells. Finally, we found several transcription regulation factors, such as AP2-α, MZF1-4, n-Myc, and c-ETS, which located on the CpG island of CDH13 promoter region, have been hypermethylated in all 20 CpG sites in HA22T cell line. It may alter the regulation of transcription factors in CDH13 gene expression.

目錄
圖次
表次
中文摘要 1
緒言 3
壹、 文獻探討
一、肝癌--台灣地區人民生命健康的威脅
4
(一) 肝癌的成因
(二) 肝癌的症狀、診斷與治療 5
10
二、癌症的發生
(一) 癌症發生的過程
(二) 基因與癌症的生成
(三) 染色體缺失與腫瘤抑制基因
(四) 肝細胞癌的染色體異質性消失偵測
(五) 人類第十六號染色體異質性消失與肝細
胞癌發展有關
11
14
25
27
30
三、DNA甲基化修飾與癌症的生成
(一) DNA甲基化修飾與基因活性的調節
(二) 腫瘤抑制基因甲基化修飾與癌症的生成
32
42
貳、 材料與方法
一、組織與細胞株樣本之取得與保存
(一) 肝臟腫瘤組織之取得與保存
(二) 肝癌細胞株之取得與保存
44
44
二、偵測肝臟腫瘤組織與肝癌細胞株DNA甲基化狀
態
(一) 肝臟腫瘤組織DNA萃取
(二) 萃取肝癌細胞株DNA
(三) 對照組DNA甲基化處理
(四) DNA之亞硫酸鈉化學修飾
(五) 甲基化特異性PCR分析
(六) 甲基化特異性核酸定序分析
46
48
48
49
49
55
三、肝臟腫瘤組織與肝癌細胞株CDH13 RNA表現
之分析
(一) 萃取肝臟腫瘤組織與肝癌細胞株RNA
(二) 反轉錄聚合酶連鎖反應
(三) 北方點墨法
56
57
59
四、肝癌細胞株CDH13蛋白表現之分析
(一) 萃取總蛋白
(二) 分離膜蛋白與胞內蛋白
(三) SDS-PAGE蛋白質電泳
(四) 西方點墨法
60
61
62
64
五、肝癌組織檢體切片之CDH13蛋白組織免疫呈色
分析 65
參、 結果與討論
一、以甲基化特異性PCR分析肝臟腫瘤組織中第十
六號染色體上腫瘤抑制基因群之甲基化狀態
二、偵測CDH13基因於肝癌生成中是否受基因甲基
化影響
(一) CDH13 mRNA於正常組織內之表現量分
析
(二) CDH13 mRNA於肝癌腫瘤組織之表現量
分析
67
77
78
三、偵測CDH13基因於肝癌細胞株內的甲基化狀態以及基因表現
(一) 以甲基化特異性PCR分析肝癌細胞株中
CDH13基因之甲基化狀態
(二) CDH13 mRNA於肝癌細胞株之表現量分
析
81
82
四、偵測CDH13蛋白於肝癌細胞株間的表現量差異與細胞上之表現位置
(一) CDH13蛋白於肝癌細胞株間之表現量差
異分析
(二) CDH13蛋白分布於肝癌細胞之位置表現
分析
84
87
五、偵測CDH13蛋白於不同肝炎病毒感染之肝癌組織病理切片中的表現位置 88
六、CDH13基因調節區之甲基化特異性定序分析(MS-sequencing)與轉錄作用因子結合位之預測 93
肆、 結論 97
伍、 參考文獻 100
英文摘要 121
圖次
圖1. 行政院衛生署九十一年度歷年死亡統計 6
圖2. 二十二對染色體異質性消失在22位肝細胞癌病患的發生頻率 29
圖3. 胞嘧啶的甲基化添加 33
圖4. 銘印基因的甲基化修飾 37
圖5. H19與Igf2銘印基因的調控機制 38
圖6. DNA甲基化修飾對基因表現的調控作用 40
圖7. 人類組織與腫瘤細胞株中端粒酶活性、hTERT基因表現與甲基化狀態 41
圖8. 基因體DNA經亞硫酸鈉化學修飾之機制 52
圖9. 人類第十六號染色體上之腫瘤抑制基因之分佈圖 53
圖10. 剖析TSC2基因於肝癌檢體之DNA甲基化狀態 68
圖11. 剖析SOCS1基因於肝癌檢體之DNA甲基化狀態 70
圖12. 剖析CDH1基因於肝癌檢體之DNA甲基化狀態 72
圖13. 剖析E2F4基因於肝癌檢體之DNA甲基化狀態 74
圖14. 剖析CDH13基因於肝癌檢體之DNA甲基化狀態 76
圖15. 利用北方點墨法分析CDH13 mRNA於正常組織內之表現量 79
圖16. 利用RT-PCR偵測 CDH13 mRNA於肝癌腫瘤組織與正常肝組織之表現量 80
圖17. 偵測肝癌細胞株之CDH13基因甲基化狀態與mRNA表現 83
圖18. CDH13初級蛋白結構示意圖 85
圖19. CDH13蛋白於肝癌細胞株間之表現量差異分析 86
圖20. CDH13蛋白於肝癌細胞株之細胞質與細胞膜分布情形 89
圖21. 肝癌組織病理切片上肝細胞之CDH13蛋白免疫組織化學呈色分析 91
圖22. 肝癌組織病理切片上血管系統之CDH13蛋白免疫組織化學呈色分析 92
圖23. CDH13基因調節區的可能轉錄作用因子結合位 95
圖24. CDH13基因甲基化特異性核酸定序分析 96
附圖1. 利用基因晶片剖繪人類基因庫於十二種人類正常組織內之CDH13 mRNA表現量
99
表次
表1 行政院衛生署九十一年度台灣地區主要癌症死亡統計。 7
表2 第十六對染色體異質性消失與原發性肝細胞癌病患臨床與病理參數之關係表 31
表3 MS-PCR與定序使用之primer的序列、夾擊區大小與接合溫度條件 54

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