摘要
根據統計全世界大約有 6 億人口有嚼食檳榔的習慣，在 2004 年國際癌症研究機構指出嚼食檳榔不含菸草，對人類是一級致癌物，且檳榔果本身也同為一級致癌物。台灣地區嚼食檳榔是非常普遍的習慣，估計在台灣大約有二百萬的檳榔嚼食者，約占台灣地區總人口數的百分之十。過去研究顯示嚼食檳榔不單只是造成口腔潛在惡性病變或口腔癌的一個重要危險因子，亦可能會造成其他的癌症或健康危害。經由測定檳榔果之生物鹼後，發現每天檳榔的嚼食量可能與檳榔嚼食者血液中檳榔鹼或檳榔次鹼的濃度呈現顯著性線性正相關。經過微陣列晶片分析後，選定檳榔對癌症發生及癌化過程中具顯著表現的候選基因 MAO-A 為研究對象。在人類口腔正常組織與癌化組織的初步分析結果顯示，MAO-A 在口腔癌組織中有低度調控的情形，亦揭露檳榔嚼食且罹患口腔癌的患者可能與 MAO-A 的基因型有關。以檳榔鹼及檳榔果萃取物投藥於口腔正常細胞 HGF 能誘導 MAO-A 表現量上升，但是在口腔癌化細胞 Ca9-22 與 SAS 中 MAO-A 表現量卻降低，且單一核苷酸多態性的分析結果亦顯示 MAO-A 基因與口腔癌化發生有關。未來的研究方向將釐清檳榔使用者其 MAO-A 基因相關的蛋白質體學表現，並進而推論其可能的功能及分子機轉，以預防檳榔所引起的口腔潛在惡性病變及口腔癌。

Globally, there are about 600 million betel quid chewers. In 2004, the International Agency for Research on Cancer had declared betel quid (BQ) chewing without tobacco is carcinogenic to humans, and areca nut (AN) itself is also carcinogenic to humans. This practice is widespread in Taiwan, with approximately two million habitual users, about 10% of Taiwan population. From past studies, BQ chewing is a risk factor not only for oral potentially malignant disorders (OPMDs) and oral cancer, but other cancers or adverse health effect. The quantity of habitual BQ use (quids/per day) positive correlated significantly with blood concentration of arecoline and arecaidine, the two major alkaloids in AN. A microarray chip analysis shows a candidate gene MAO-A which is significant to betel nut caused the process of cancer. The preliminary results suggested MAO-A gene variants may be associate with oral cancer risk. From human paired oral tissue, we also confirmed the MAO-A expression was consistently lower in cancerous tissues than adjacent non-cancerous tissue. Arecoline and areca nut extracts treated HGF cells shows an increased expression of MAO-A, but treated Ca9-22 and SAS cells is decreased. And the results of SNP analysis suggest that MAO-A gene polymorphism may associated with the mechanism of oral cancer. These findings implied us to new directions for studying the proteomics of MAO-A metabolizing mechanism in BQ-induced OPMDs and oral cancer in the future.

論文審定書 i
致謝 ii
中文摘要 iii
英文摘要 iv

壹、序言 (Introduction) 1
背景介紹 1
一、檳榔 2
1. 檳榔的組成 2
1.1檳榔子 2
1.2 荖花 3
1.3 荖葉 3
1.4 荖藤 3
1.5 紅灰與白灰 3
2. 檳榔對人體健康的危害 3
2.1 口腔黏膜纖維化症 5
2.2 口腔黏膜白斑症 6
2.3 口腔黏膜紅斑症 6
3. 檳榔對自然環境的危害 7
二、口腔癌 7
1. 口腔癌的形成原因 8
2. 口腔癌的臨床症狀 8
3. 口腔癌的臨床分期 9
4. 口腔癌的治療方式 10
5. 口腔癌的預防與自我檢查 10
三、口腔癌的生物標記 11
四、檳榔生物鹼及相關成分對健康的影響 12
1. 生物鹼對口腔黏膜之影響 13
2. 生物鹼對細胞外基質之影響 14
2.1 對基質金屬蛋白酶之影響 14
2.2 對纖維蛋白溶酶原激活物之影響 15
2.3 對成纖維細胞活性之影響 15
3. 生物鹼與尼古丁對口腔黏膜病變之影響 16
4. 單寧對細胞外基質之影響 16
5. 銅離子對口腔黏膜纖維化之影響 16
五、Monoamine oxidase 17
1. Monoamine oxidase A (MAO-A) 18
2. Monoamine oxidase A (MAO-A) 基因與癌症的相關性研究 19

貳、實驗目的 (Specific Aims) 21

參、實驗流程 (Experiment Flowchart) 21

肆、材料與方法 (Materials and Methods) 23
1. 臨床檢體來源 23
2. 口腔正常與癌化細胞株 HGF、Ca9-22 及 SAS 之培養與處理 23
2.1 細胞株 23
2.2 藥品與試劑 23
2.3 培養液配置 24
2.3.1 HGF細胞株培養液配置 24
2.3.2 Ca9-22細胞株培養液配置 24
2.3.3 SAS 細胞株培養液配置 25
2.4 Phosphate-Buffered Saline (PBS) 10X 25
2.5 Trypsin-EDTA 1X 25
2.6 細胞解凍程序 25
2.7 細胞繼代培養 26
2.8 細胞計數 27
2.9 細胞冷凍程序 27
3. MTT 細胞存活率測試 27
3.1 細胞計數與種植 27
3.2 檳榔鹼及檳榔果萃取物之藥物處理 28
3.3 MTT 試劑處理 28
3.4 DMSO 試劑處理 29
3.5 ELISA Reader 29
4. 口腔正常與癌化細胞之 RNA 處理 30
4.1 細胞 Total RNA 萃取 30
4.2 Total RNA 濃度測定 31
4.3 將 mRNA 反轉錄成 cDNA 31
4.4 即時定量聚合酶連鎖反應 32
5. 口腔正常與癌化細胞之組織蛋白質處理 34
5.1 口腔正常與癌化組織蛋白質萃取 34
5.2 口腔正常與癌化細胞株 HGF、Ca9-22 及 SAS 蛋白質萃取 34
5.3 實驗溶液配置 35
5.4 蛋白質濃度測定 35
6. 蛋白質電泳試驗 36
6.1 聚丙烯醯胺膠體配置 36
6.2 西方墨點法 37
6.3 Stripping 39
6.4 Coomassie Brilliant Blue G-250 stain 40
7. MAO-A Genotyping 40
8. 統計分析 41

伍、實驗結果 (Results) 42
1. 檳榔鹼(Arecoline)對口腔細胞的存活分析 42
2. 檳榔鹼(Arecoline)在口腔細胞中對MAO-A基因的表現 42
3. 檳榔鹼(Arecoline)在口腔細胞中對MAO-A蛋白質的表現 43
4. 檳榔果萃取物(Areca nut extracts)對口腔細胞的存活分析 44
5. 檳榔果萃取物(Areca nut extracts)在口腔細胞中對MAO-A基因的表現 45
6. 檳榔果萃取物 (Areca nut extracts) 在口腔細胞中對MAO-A蛋白質的表現 45
7. 口腔癌化組織及其鄰近正常組織內 MAO-A 的表現差異 46
8. MAO-A 之單一核苷酸點變異 (single nucleotide polymorphisms, SNP) 對口腔癌之風險 47

陸、討論 (Discussion) 49
1. 檳榔鹼及檳榔果萃取物對口腔細胞之毒殺作用 49
2. 檳榔鹼及檳榔果萃取物對 MAO-A 基因之誘導 51
3. 檳榔鹼及檳榔果萃取物對口腔細胞中 MAO-A 蛋白質之誘導 52
4. 在口腔癌鄰近組織中 MAO-A 蛋白質之誘導 54
5. 基因變異與致癌物的使用對口腔癌之風險 55

柒、參考文獻 58

捌、圖表 (Figures and Tables Contents) 66
Figure 1. Effect of arecoline on the viability of HGF, Ca-922 and SAS cells. 66
Figure 2: The mRNA expression of MAO-A after arecoline treatment at different concentrations (0, 50, 100, 200, 400, and 800 μM). 68
Figure 3: The protein expression of MAO-A after arecoline treatment at different concentrations (0, 50, 100, 200, 400, and 800 μM). 70
Figure 4. Effect of areca nut on the viability of HGF, Ca-922 and SAS cells.
72
Figure 5: The mRNA expression of MAO-A after areca nut treatment at different concentrations (0, 50, 100, 200, 400, and 800 μM). 74
Figure 6: The protein expression of MAO-A after areca nut treatment at different concentrations (0, 50, 100, 200, 400, and 800 μM). 76
Figure 7. Protein level of MAO-A in human oral squamous cell carcinoma tissue (T) and its adjacent normal tissues (N). 78
Table 1. Basic information of oral cancer patients. 79
Table 2: Distribution of subjects with MAO-A types between oral and pharyngeal cancer, OPMD patients, and healthy controls. 80

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