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博碩士論文 etd-0615113-102942 詳細資訊
Title page for etd-0615113-102942
論文名稱
Title
CYP26B1 及相關蛋白質在檳榔引發口腔癌之研究
Study of CYP26B1 and associated proteins in betel quid induced oral cancers
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
88
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2013-06-28
繳交日期
Date of Submission
2013-07-21
關鍵字
Keywords
檳榔鹼、檳榔子、CYP26B1、嚼食檳榔、口腔癌、蛋白質體學
Betel Quid, Arecoline, CYP26B1, Areca nut, Oral cancer, Proteomic
統計
Statistics
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The thesis/dissertation has been browsed 5709 times, has been downloaded 1 times.
中文摘要
全球目前大約有6 億人口有嚼食檳榔的習慣。2004 年國際癌症研究機構指出嚼食檳榔不含菸草對人類是第一級致癌物,且檳榔子本身也同為第一級致癌物。台灣地區嚼食檳榔是非常普遍的習慣,據估計大約有二百萬人為檳榔習慣性使用者,約佔台灣總人口數百分之十。先前研究結果顯示,每天的檳榔嚼食量與檳榔嚼食者血液中檳榔鹼與檳榔次鹼的濃度呈現顯著性正相關,經廣泛基因組微陣列晶片分析選定檳榔對口腔病變發生及癌化過程中顯著的候選基因 CYP26B1 為研究標的。針對人類口腔正常組織與癌化組織的分析結果顯示,CYP26B1 在口腔癌症組織中有著高度表現,而CYP26B1 基因多型性與口腔潛在惡性病變及口腔癌之形成風險有關,揭露檳榔嚼食者之口腔癌化可能與 CYP26B1 的基因表現特性有關。更進一步以檳榔鹼投予口腔正常細胞 HGF 與口腔癌化細胞 Ca-922 能誘導 CYP26B1 表現量顯著性上升,CYP26B1 經檳榔鹼誘導後高達 2.7 倍 (HGF)與 3.1 倍 (Ca-922),而 CYP26B1 splicing variant 達 1.6 倍 (HGF) 與 1.9 倍(Ca-922),顯示檳榔鹼對 CYP26B1 及其 splicing variant 有差異性的誘導現象,此研究結果揭露 CYP26B1 基因可能跟檳榔物質所造成的損傷有關。蛋白質體學研究結果揭露以檳榔鹼投予 Ca-922 會使五個蛋白質表現量下降與26 個蛋白質表現量上升,其中 adenosine deaminase、T-complex protein、14-3-3 protein 已被報導與口腔癌的惡化程度及放射線療法的抗性有關。未來在蛋白質體的相關蛋白質研究將進一步釐清檳榔鹼導致口腔癌的相關分子機轉。
Abstract
Approximately 600 million people in the world chew betel quid (BQ). In 2004, the International Agency for Research on Cancer (IARC) declared BQ chewing without tobacco and the areca nut to be carcinogenic to humans. The practice of BQ chewing is widespread in Taiwan, approximately two million people, which is 10% of the Taiwanese population, are habitual users. Previous studies have indicated that the
quantity of habitual BQ use (quids/d) is significantly positively correlated with an increase in the blood concentration of arecoline and arecaidine, the two major alkaloids in areca nut. In a previous study, a genome-wide microarray chip assay showed that a candidate gene, CYP26B1, which is particular to BQ, may cause oral cancer. CYP26B1 and spliced variant levels had increased in the arecoline-treated oral
cancer cell line Ca-922 and normal cells HGF. Based on an analysis of human oral cancer and normal tissues, our data confirmed that CYP26B1 gene expression was consistently higher in cancerous tissues compared with non-cancerous tissues, In addition, the variant of the CYP26B1 gene polymorphism may contribute to genetic susceptibility to oral potentially malignant disorders and oral cancer. These results
suggested that the CYP26B1 gene may be associated with BQ-induced oral cancer. A proteomic study that used 2D-PAGE revealed that 5 proteins were down-regulated and 26 proteins were up-regulated in arecoline-treated oral cancer cells, in which adenosine deaminase, T-complex protein, and 14-3-3 protein were reported to be associated with oral cancer malignancies and radiotherapy resistance. Further proteomic studies may reveal the underlying molecular mechanisms of arecoline-induced in oral cancer.
目次 Table of Contents
論文審訂書 I
致謝
II
摘要
III
Abstract
IV
Abbreviation V

壹、序言 (Introduction) 1
背景介紹 1
一、 檳榔 2
1. 檳榔之組成成分 2
2. 檳榔嚼食之流行情況 4
3. 檳榔對口腔健康的危害 4
3.1 口腔黏膜纖維化 5
3.2 口腔黏膜白斑症 6
3.3 口腔黏膜紅斑症 6
二、 口腔癌 6
1. 口腔癌的成因 7
2. 口腔癌的症狀 8
3. 口腔癌的臨床分期 8
三、 口腔癌預測之生物標記 9
四、 檳榔鹼對人體的影響 11
1. 檳榔鹼對口腔黏膜的病理機轉 11
1.1 生物鹼對胞外基質的影響 12
1.1.1 對基質金屬蛋白酶及其抑制物的影響 12
1.1.2 對纖維蛋白溶酶原激活物及其抑制影響 12
1.1.3 抑制纖維細胞的吞噬活性 13
1.1.4 檳榔鹼與尼古丁對口腔黏膜病變的協同作用 13
1.2 單寧對細胞外基質的影響 13
1.3 銅與口腔纖維化中的關係 14
五、 Cytochrome P450 14
1. Cytochrome P450 26B1 15
2. CYP26B1 與口腔癌的關係 16
貳、 實驗目的 (Specific Aims) 17
參、 實驗流程 (Experiment Flowchart) 17
肆、 材料與方法 (Materials and Methods) 19
1. 臨床檢體來源 19
2. 口腔正常與癌化細胞及組織蛋白質處理 19
2.1 口腔正常與癌化組織蛋白質萃取 19
2.2 口腔正常與癌化細胞株 HGF、Ca-922 蛋白質萃取 19
2.3 實驗溶液配置 20
2.4 蛋白質濃度測定 20
3. 口腔正常與癌化細胞株 HGF、Ca-922 之培養與處理 21
3.1 細胞株 21
3.2 藥品與試劑 21
3.3 培養液配置 21
3.4 Phosphate-Buffered Saline 10X stock 22
3.5 Trypsin-EDTA 1X 22
3.6 細胞解凍程序 22
3.7 細胞繼代培養 22
3.8 細胞冷凍程序 23
3.9 細胞計數 23
4. 口腔正常與癌化細胞之 RNA 處理 24
4.1 Total RNA 萃取 24
4.2 Total RNA 濃度測定 24
4.3 將 mRNA 反轉錄成 cDNA 25
4.4 PCR 聚合酶連鎖反應 25
5. MTT 細胞存活率測試 26
5.1 細胞計數與種植 26
5.2 檳榔鹼藥物處理 26
5.3 MTT 試劑處理 27
5.4 DMSO 試劑處理 27
5.5 ELISA Reader 27
6. 蛋白質電泳試驗 28
6.1 聚丙烯醯胺膠體配置 28
6.2 西方墨點法 28
6.3 Stripping 29
7. 蛋白質體試驗 30
7.1 TCA/Acetone 蛋白質沉澱 30
7.2 蛋白質回溶 31
7.3 Isoelectric focusing electrophoresis 31
7.4 Immobiline DryStrip Equilibration 32
7.5 Sodiumdodecylsulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) 32
7.6 Silver stain 33
7.7 Coomassie Brilliant Blue G-250 stain 34
7.8 Gel imaging analysis 35
7.9 In gel digestion 35
7.10 蛋白質身分鑑定 36
8. CYP26B1 Genotyping 36
9. 統計分析 36
伍、 實驗結果 (Result) 37
1. 檳榔鹼 (Arecoline) 對口腔細胞的存活影響 37
2. 鑑定 CYP26B1 and CYP26B1 spliced variant 在口腔細胞的表現 37
3. 檳榔鹼 (Arecoline) 對 CYP26B1 and CYP26B1 spliced variant 的誘導能力 38
4. 口腔正常組織與癌症組織內 CYP26B1 spliced variant 的表現差異 39
5. 二維電泳與軟體比對之分析結果 39
6. 差異性蛋白質身份鑑定 40
7. CYP26B1 單一核苷酸變異對口腔潛在惡性病變與口腔癌之風險 41
陸、 結果討論 (Discussion) 43
1. 檳榔鹼對口腔細胞株毒殺效果 43
2. CYP26B1 and CYP26B1 spliced variant 44
3. 檳榔鹼 (Arecoline) 誘導 CYP26B1 and CYP26B1 spliced variant 表現 44
4. CYP26B1 spliced variant 在口腔癌組織表現上升 45
5. 差異性蛋白質 46
6. CYP26B1 單一核苷酸變異與物質使用對口腔癌之風險 48
柒、 結論 (Conclusion) 50
捌、 參考文獻 (Reference) 51
玖、 圖表 (Figures and Tables Contents) 65
Figure 1. Effect of arecoline on the viability of HGF and Ca-922 cells. 65
Figure 2. Expression of CYP26B1 and CYP26B1 spliced variant in HGF and Ca-922 cell line. 67
Figure 3. Arecoline induced up-regulation of monooxygenases, Cytochrome P450 family 26 subfamily B polypeptide 1 (CYP26B1). 68
Figure 4. Protein level of CYP26B1 spliced variant in human oral squamous cell carcinoma tissue (T) and its adjacent normal tissues (N). 70
Figure 5. 2-DE analysis of arecoline treated oral normal cell line HGF. 72
Figure 6. 2-DE analysis of arecoline treated oral cancer cell line Ca-922. 73
Figure 7. 2-DE analysis of oral tumor tissues. 74
Table 1. Identification of 5 down-regulated and 26 up-regulated proteins after arecoline treatment of Ca-922 oral cancer cell line. 75
Table 2. Distribution of CYP26B1 genotype and allele frequency in oral cancer patients and controls. 77
TTable 3. Distribution of CYP26B1 genotype and allele frequency in oral potentially malignant disorders (OPMDs) patients and controls. 78
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