細胞凋亡可移除因遺傳基因受損的細胞，因此可以防止受損細胞進入不受控制的細胞增生或轉形為癌細胞。細胞凋亡分為外在death receptor路徑及內在mitochondrial路徑，並由許多細胞凋亡基因所調控包括Fas，survivin，caspases等。在本論文中，我們執行一個以醫院為底(hospital-based)的病例對照研究，探討Fas相關凋亡路徑相關的七個基因(Fas, FasL, survivin, XIAP, caspase-3, caspase-8與caspase-9)之基因多型性與口腔鱗狀上皮細胞癌之相關性。自2003年到2006年間，我們於高雄榮民總醫院收集共279名新診斷的口腔鱗狀上皮細胞癌病人和469名健康配對，再以聚合酶連鎖反應-限制酶片段長度多型性(PCR-RFLP)技術完成基因型的分析。我們的結果顯示在所有分析的八個基因型中，只有FasL -844TT基因型與口腔鱗狀上皮細胞癌具有相關性 (P=0.047)。另外，研究發現當Fas相關凋亡路徑基因的高危險性基因型數目增加時，口腔鱗狀上皮細胞癌危險性的趨勢逐漸增加，且呈劑量效應 (P for trend, 0.034)。在研究基因與環境的相互作用方面，我們有三個發現：(1) FasL T-844C與survivin 轉譯區之Lys129Glu基因多型性在閔南人為危險因子但不在其他分析的族群，且統計上具差異性(P=0.023及P=0.014)。(2) caspase-3 A21926C與survivin轉譯區之129Lys/Glu基因多型性在不抽煙者具保護效果且具統計差異(P=0.047及P=0.024)。(3) caspase-9轉譯區之Arg221Gln基因多型性可能對吃檳榔者為重要的危險因子(P=0.048)。因此，我們推測Fas相關凋亡路徑基因的多型性可能在口腔鱗狀上皮細胞癌危險性上扮演重要角色。此外，我們特別針對口腔癌中發生比例最高之口腔頰黏膜鱗狀上皮細胞癌進行預後因子研究。以免疫組織化學染色法(IHC)分析頰黏膜鱗狀上皮細胞癌樣本的caspase-3及p53蛋白質表現，並研究蛋白質表現與臨床病理特質以及疾病存活的關係。檢體來源為1990年至2005年於高雄榮民總醫院接受切片檢查或手術治療的病人，共117名。結果顯示，頰黏膜惡性腫瘤的五年存活率、十年存活率以及十四年存活率分別為62%，39%與18%。而頰黏膜鱗狀上皮細胞癌的存活與細胞分化、病理分期、腫瘤大小、淋巴結轉移、手術後的放射線或化學治療及嚼食檳榔的狀態皆有關。更重要的是在單變項或多變項分析上，細胞質中之caspase-3的正向表現為頰黏膜鱗狀上皮細胞癌不利的預後因子。由本論文結果可知Fas相關凋亡路徑基因多型性的共同效應及基因與環境的相互作用可能在口腔鱗狀上皮細胞癌危險性上扮演重要角色。另外，caspse-3細胞質的表現情況可作為頰黏膜鱗狀上皮細胞癌的預後指標。

One of the physiological functions of apoptosis is to eliminate cells that have sustained genetic aberrations, thereby preventing damaged cell from attaining uncontrolled cell proliferation or transformation into carcinoma. The apoptotic response is mediated by many apoptotic genes including Fas, survivin, caspases etc. through either the extrinsic pathway (death receptor pathway) or the intrinsic pathway (mitochondrial pathway). In this dissertation, we carried out a hospital-based case-control study to investigate the association between seven Fas related apoptosis pathway genes (Fas, FasL, survivin, XIAP, caspase-3, caspase-8 and caspase-9) and the risk for oral squamous cell carcinoma (OSCC). In this study, 279 newly diagnosed OSCC patients and 469 frequency-matched controls were recruited at Kaohsiung Veterans General Hospital from 2003 to 2006. Total eight various polymorphisms in seven genes mentioned above were examined by PCR-RFLP and our results showed that only FasL –844TT genotype (P=0.047) was associated with the risk of OSCC. However, a trend of increased risk of OSCC was found in people with the increasing putative high-risk genotypes of Fas related apoptosis pathway genes (P for linear trend, 0.034). From our results of the gene-environment interaction analyses, three important observations were listed below: (1) the polymorphism of both FasL T-844C and survivin codon Lys129Glu were risk factors for Fukienese (P=0.023 and P=0.014, respectively), but not for other ethnicities examined. (2) For non-smokers, survivin codon Lys129Glu and caspase-3 A21926C polymorphisms had significant protect (P=0.047 and P=0.024, respectively). (3) For betel quid (BQ) chewers, caspase-9 codon Arg221Gln polymorphism was an important risk factor (P=0.048). Together, the results suggested that gene polymorphisms of Fas related apoptosis pathway were associated with the risk of OSCC. In order to evaluate the relationship between p53 and caspase-3 protein expression levels or clinicopathologic characteristics and survival outcome in OSCC, we examined the protein expression profilings of caspase-3 and p53 in those patients with buccal mucosa squamous cell carcinoma (BMSCC). Total 117 primary buccal carcinoma specimens were collected at KSVGH between 1990 and 2005 and their paraffin-embedded tissues were sectioned and subjected for immunohistochemistry examination. The overall cumulative survival rate was 62% for 5-years, 39% for 10-years and 18% for 14-years, respectively. Ours results showed that the survival rate of BMSCC was significantly correlated with all clinicopathological characteristics including cell differentiation, pathological stage, tumor size, lymph node metastasis, post-operative RT, post-operative CT and BQ chewing status. Most importantly, the high caspase-3 protein level in cytoplasm was an unfavorable prognostic factor in the univariate or the multivariate analysis. In conclusion, the join effect of genetic polymorphisms of Fas related apoptosis pathway genes and gene-environment combined effect may play important roles in the OSCC risk. In addition, high caspase-3 protein expression in cytoplasm may be used as a prognostic marker for patients with BMSCC.

Page
Chapter 1
General Introduction 1
1.1 Backgrounds and Significance 2
1.2 Specific Aims 15
1.3 References 16
Chapter 2
The Relation of Polymorphisms in Fas Related Apoptosis Pathway Genes to Oral Squamous Cell Carcinoma Risk: A Case-Control Study. 24
2.1 Summary 25
2.2 Introduction 26
2.3 Patients and Methods 33
2.4 Results 36
2.5 Discussion 41
2.6 References 48
Tables 59
Figures and Figure Legends 70
Chapter 3
The Relation of the Caspase-3 and p53 Expression Patterns with the Prognosis of Buccal Mucosa Squamous Cell Carcinoma: A Retrospective Cohort Study 73
3.1 Summary 74
3.2 Introduction 75
3.3 Patients and Methods 78
3.4 Results 82
3.5 Discussion 85
3.6 References 89
Tables 95
Figures and Figure Legends 103
Chapter 4 Future Perspectives 112
4.1 Specific Aims 113
4.2 Experimental Designs 114
4.3 References 116

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