DNA錯誤配對修補基因的功能缺失與部分癌症的病理成因和預後有關，尤其是在hMLH1和hMSH2基因喪失功能時。目前偶發性癌症之研究報告並未發現hMLH1基因的複製錯誤表現型與其突變之間有關聯，由此推測hMLH1基因的不活化卻可能與其啟動子(promoter)高度甲基化有關。因此本研究的目的其一是探討口腔癌的hMLH1啟動子高度甲基化和hMLH1蛋白質表現的關聯性。我們的結果發現，當利用甲基化特異性PCR (methylation-specific PCR)測定hMLH1啟動子的甲基化情形時，75名(100%)個案的啟動子皆無甲基化，但以HpaII為基礎之多重PCR (HpaII-based PCR)測定時，99名個案中有19名(19.2%)的啟動子有部分甲基化的現象。此外，在92名口腔鱗狀上皮細胞癌病患中，發現24名 (26.1%)的hMLH1蛋白質表現減少，但在hMLH1蛋白質表現和其啟動子的甲基化的一致性分析上，並未發現二者的相關性。
目的其二是探討在口腔鱗狀上皮細胞癌hMLH1和hMSH2蛋白質於病理成因的意義。我們摘錄了高雄榮民總醫院92名口腔鱗狀上皮細胞癌病患的臨床病理資料，並以免疫組織化學染色法測定其hMLH1和hMSH2蛋白質表現，發現92名個案中有24 名(26.1%)的hMLH1蛋白質表現減少，但只有10名 (10.9%)的hMSH2蛋白質表現減少。此外發現，hMLH1蛋白質表現減少與腫瘤分化及其淋巴轉移具有統計意義，但並未發現hMSH2蛋白質表現與其臨床病理資料有相關性。
最後，由於先前研究報導指出hMLH1和Aurora-A基因與數種癌症的預後有直接關係，我們以免疫組織化學染色法測定138名病理證實為原發頰黏膜口腔癌病患的腫瘤檢體hMLH1和Aurora-A蛋白質的表現程度，並分別評估與其臨床病理資料及存活之相關性。我們的結果發現，138個腫瘤切片中有15個(10.9%)喪失hMLH1蛋白質表現，但此現象與其臨床病理及預後皆無相關性。另外，138個腫瘤切片中有118個 (85.5%)的Aurora-A蛋白質表現增加，且此現象與病理分期及腫瘤大小具有統計意義，但與其預後無相關性。
綜合而論，口腔癌的hMLH1啟動子甲基化對其基因的表現，可能並非扮演重要的角色。然而，口腔鱗狀上皮細胞癌的發展與hMLH1基因的表現缺失具有統計意義，但與hMSH2基因的表現並無相關。此外，Aurora-A蛋白質的表現可能影響頰黏膜口腔癌的惡化反應，但hMLH1蛋白質則不會影響之，並且二者可能皆非影響頰黏膜口腔癌的預後因子。

Defects in mismatch repair genes, particularly the hMLH1 and hMSH2 genes, are associated with pathogenesis and prognosis of some cancers. The lack of correlation between replication error phenotype and mutations in hMLH1 in sporadic human cancers suggested that inactivation of the hMLH1 gene may be associated with promoter hypermethylation. This study was to investigate the association of hMLH1 promoter hypermethylation and hMLH1 protein expression in oral cancer. Our results indicated that all 75 cases (100%) were without any methylation of hMLH1 promoter by use of methylation-specific PCR (MSP). Nineteen of 99 cases (19.2%) were partial methylation by HpaII-based PCR. In addition, 24 (26.1%) of 92 cases of OSCC had reduced levels of hMLH1 protein. The concordance analysis showed that the expression level of hMLH1 protein was not correlated with methylation of hMLH1 promoter.
Furthermore, the prognosis significance of hMLH1 or hMSH2 proteins on OSCC was also investigated. We analyzed the association of hMLH1 and hMSH2 protein expression with clinicopathological data of 92 cases of OSCC at KSVGH. We found that 24 (26.1%) of 92 cases of OSCC had reduced levels of hMLH1 protein, however only 10 cases (10.9%) had reduced hMSH2 by use of IHC. In addition, the reduced expression of hMLH1 correlated with the tumor differentiation and N classification. However, none of these clinical and pathological characteristics of the OSCC patients were associated with the extent of hMSH2 expression.
Finally, previous studies reports that the hMLH1 and Aurora-A are directly involved in the prognosis of several cancers. The expression levels of hMLH1 and Aurora-A protein were investigated in the 138 tumor samples for consecutive patients with pathological confirmed primary buccal carcinoma (BC). Then the association of the protein expression with clinicopathological data and survival were also evaluated. The loss of hMLH1 protein was found in 15 (10.9%) of 138 tumor sections by IHC. In addition, loss of hMLH1 protein expression was not any correlated with clinical features and patients’ prognosis. The up-regulation of Aurora-A protein was found in 118 (85.5%) of 138 tumor sections by IHC. In addition, the up-regulation of Aurora-A protein expression was correlated with the pathological stage and T classification, but Aurora-A protein up-regulation was not correlated with prognosis.
In conclusion, promoter methylation of hMLH1 might not play a potent role in the gene expression in oral cancer. Defective expression of hMLH1 but not hMSH2 was associated with the development of OSCC. In addition, the Aurora-A protein expression but not hMLH1 may affect the malignant behavior of BC. However, the hMLH1 and Aurora-A protein expression might be not the prognostic factors for BC patients.

Contents………………..…………………………………………………………... 1
Abbreviations……………...……………………………………………………...... 3
中文摘要……....……………..……………………………………………………. 4
Abstract……….………………..…………………………………………………... 6
Chapter 1
General Introduction
1.1 Backgrounds and Significance…………………………………………... 9
1.2 Specific Aims……………………………………………………………. 27
1.3 References……………………………………………………………….. 28
Chapter 2
hMLH1 Protein Expression and Promoter Methylation in Oral Squamous Cell Carcinoma
2.1 Summary………………………………………………………………… 36
2.2 Introduction……………………………………………………………… 38
2.3 Materials and Methods…………………………………………………... 42
2.4 Results…………………………………………………………………… 55
2.5 Discussion……………………………………………………………….. 59
2.6 References……………………………………………………………….. 63
Tables
Figures and Figure Legends
Chapter 3
The Association between hMLH1 and hMSH2 Protein Expression and Clinical Outcome in OSCC
3.1 Summary………………………………………………………………… 86
3.2 Introduction……………………………………………………………… 87
3.3 Materials and Methods…………………………………………………... 90
3.4 Results…………………………………………………………………… 95
3.5 Discussion……………………………………………………………….. 98
3.6 References……………………………………………………………….. 101
Tables
Figures and Figure Legends
Chapter 4
The Association between hMLH1 and Aurora-A Protein Expression and Clinical Prognosis in Buccal Cancer
4.1 Summary………………………………………………………………… 116
4.2 Introduction……………………………………………………………… 117
4.3 Materials and Methods…………………………………………………... 122
4.4 Results…………………………………………………………………… 126
4.5 Discussion……………………………………………………………….. 131
4.6 References……………………………………………………………….. 135
Tables
Figures and Figure Legends

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