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研究生:葉建陽
研究生(外文):Chien-Yang Yeh
論文名稱:不同口腔習慣與淋巴球亞群於口腔癌進行之角色
論文名稱(外文):Effect of different oral habits and lymphocytes subpopulation on oral cancer progression
指導教授:鄭景暉鄭景暉引用關係
指導教授(外文):Jiiang-Huei Jeng
口試委員:江俊斌許明倫
口試委員(外文):CP ChiangMing Lun Hsu
口試日期:2015-07-31
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床牙醫學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:95
中文關鍵詞:化學致癌口腔癌口腔癌前病變淋巴球細胞口腔習慣惡性轉變
外文關鍵詞:Chemical carcinogenesisoral canceroral precancerlymphocyte populationoral habitsmalignant transformation
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中文摘要
由於近幾年來,對於口腔癌患者的治療與預後仍是相當不容易的,所以我們針對台大醫院患者進行追蹤性地研究,我們試圖在口腔癌前與口腔癌病患身上找出是否與各類口腔不良習慣(抽菸、喝酒、嚼食檳榔)及淋巴球細胞亞群的相關變異,存在著相互關聯。希望藉此研究口腔癌前病變與口腔癌患者其確定相關關係,並提供顯著的方向來治療以控制惡性轉變。不少研究顯示各類的化學致癌物質可以透過多種步驟達到誘導細胞DNA的破壞,造成基因毒性,細胞增殖,組織發炎等損害。在第一部分, 我們以C3H10T1/2細胞的癌化研究更進一步表明,檳榔的咀嚼會因為檳榔子萃取液(ANE)和檳榔生物鹼的細胞毒性,在口內可能影響傷口的癒合和產生發炎病症,甚至檳榔子成分可藉由其腫瘤啟始作用在口腔粘膜下纖維化與口腔癌的進程扮演重要角色。
其次化學刺激致癌已被證明是一種多步驟的癌化進程,包括腫瘤啟始,促進,增長和許多複雜交互的過程。在第二部份,我們研究28例口腔癌前病變患者,白斑(17例),口腔黏膜下纖維化(9例),口腔扁平苔蘚(1例),和紅斑(1例),最後有10位患者轉變為口腔癌。追蹤長達10年,針對了其年齡,TNM stage,各種口腔不良習慣等,以及利用流式細胞儀分析其淋巴細胞亞群(CD4 +,CD8 +,CD19 +,CD56 +和它們的活化標記物CD25和CD69)。 我們發現年齡和飲酒的差異,在細胞癌前病變與惡性病變過程是存在顯著關係的。淋巴球細胞亞群和活化的分佈是隨著疾病的進展不同而改變,在淋巴球細胞亞群的數值分析中, CD4+CD69+, CD19+CD69+ 和 CD56+CD69+ 表現,分別與惡性病變化有著統計上的相關聯性(p<0.05)。 CD4+,CD56+CD25+ 在惡性病變患者上則被發現有上升的趨勢(p<0.1)。不良習慣在口腔癌前病變的患者中,雖然無法明顯看出其個別習慣之間有明顯的促進細胞癌化病變的現象,但反過來看,沒有不良口腔習慣的癌前病患者,會有癌化病變的比例確實較少。
在第三部份,我們同樣收集分析86例口腔癌病患,最後統計有50位患者因癌症末期而死亡,而其中3年內的死亡率更達52%。在本組的調查中,罹癌死亡年齡層的高低與其死亡的比較,僅有些微的連結但並無明顯統計上的關係。而有無喝酒習慣的影響,則跟在癌前惡性病變的研究中一樣,亦是呈現正相關的連結,這並不表示檳榔與菸害的習慣對於口腔癌的傷害較為不大,只是在母群群的研究數量不大的情況下,沒有被強烈的顯示出來而已,另外根據統計,大部分罹患口腔癌的病患多為兼具多項不良口腔習慣的刺激,也因為大多數罹癌的患者都有這些習慣,才把這項指標鈍化了。此外,針對其淋巴細胞亞群CD19,CD56在罹癌患者的死亡分析上,也出現統計上的關聯,發現CD19的表現下降特別具有明顯的統計上差異,推測在免疫系統中代表B細胞於癌末患者的身上出現顯著弱化之現象,CD56+CD69+則在死亡患者群上有上升的趨勢性表現。這些結果皆顯示免疫系統會因為疾病的發展,而有所改變。所以,年齡、口腔習慣等、與其變化中的淋巴球細胞,T細胞,B細胞和NK細胞群等指標,確實是口腔癌發病機制的關鍵。所以淋巴球細胞群相關變化的分析,未來亦會是口腔癌中預測組織惡性病變與診斷的生物參考標誌。

English Abstract
In recent years, the prognosis for oral cancer patients is unpredictable even after different treatment modalities. We try to analyze whether betel quid (BQ) chewing, alcohol consumption and smoking habits may increase the risk of oral precancer and oral cancer. In addition, lymphocyte populations in patients may potentially affect the malignant transformation of oral pre-cancer in modern studies. We attempted to study whether oral habits or changes in lymphocyte subsets can be a biomarker for malignant transformation or cancer death in a cohort of patients with oral precancer and cancer. Moreover, a number of studies have found that chemical carcinogens may induce DNA damage, genotoxicity, cell proliferation and tissue inflammation and contribute to carcinogenesis. In the first part of study, we use C3H10T1/2 cell transformation assay to study the potential carcinogenicity of areca nut (AN). We showed that ANE and arecoline are cytotoxic to cells and may possibly affect the oral wound healing response. ANE exhibited tumor initiation effect and may induce transformation of C3H10T1/2 cells by the promotion of TPA. These effects may contribute to the pathogenesis of oral submucous fibrosis and oral cancer.
Various carcinogens may play important roles in specific steps of chemical carcinogenesis by inducing DNA damage, cytotoxicity, cell proliferation, tissue inflammation, impairment of cell-cell communication. In the 2nd Part,we enrolled 28 patients with oral pre-cancer and 86 oral cancer patients were enrolled in this study and their personal information and oral habits were documented. Their lymphocyte populations (CD4+, CD8+, CD19+, CD56+ and their activation marker CD25 and CD69) were determined by flow cytometry on 2002-2004. After follow-up to Dec. 2014, patients with/without malignant transformation were recorded and evaluated their relation to oral habits and percentage of initial lymphocyte markers.
Ten pre-cancer patients developed OSCC with a mean period of malignant transformation of 6.80 ± 2.13 years. Patients with malignant transformation showed mean age of 48.40 ± 4.97 (n=10), relatively higher than patients without malignant transformation (41.56 ± 6.27, n=18) (P<0.05). An increase in population of peripheral blood mononuclear cells expressing CD4+CD69+, CD19+CD69+, and CD56+CD69+ (p<0.05) in pre-cancer patients with malignant transformation was noted. Alcohol consumption showed an association with the malignant transformation of patients with pre-cancer (P=0.03), whereas BQ and smoking showed little effect. Conversely, we can find the ratio of malignant transformation without poor oral habits will be lower than patient with poor habits. It indicates the potential influence on oral carcinogenesis.
In the 3rd part, 86 cases of oral cancer patients, researched over 10 years, we also found that the age (p<0.1) is related between the oral cancer groups, and drinking habits statistically associated with the death group (p<0.05). There is no obvious relationship between the BQ chewing and smoking habits with oral cancer death. It does not mean that BQ and smoking habit have no influence on cancer death, because most cancer patients have both of these oral habits. Lymphocyte subpopulations CD19+ (p<0.01), have significant relationship in the survival and death groups, CD56+ (p=0.05), CD56+CD69+ (p=0.06) have the upregulation tendency in the death group. A decrease of CD19+ suggests that B cell declined significantly in the late cancer patients’ body. These results are displayed human immune system may change during tumor development. Finally, the end of the 50 cancer patients died, the mortality rate more than 52% within three years.
We concluded that areca nut components can be a tumor initiator, leading to the generation of initiated cells. Age and alcohol consumption, and the early activation of T cell, B cell and NK cells are crucial in the transformation of oral precancer to oral cancer. Moreover, age, alcohol consumption, and changes in B cells and NK cells in oral cancer patients are important for prediction of their future survival. Therefore, analysis of lymphocyte populations can be a diagnosis and an extra-prediction biomarker for malignant pathogenesis of oral cancer.

CONTENT
口試委員會審定書…………………………………………….…… 2
Acknowledgment…………..……………………………………..…. 3
Chinese Abstract………………………………………..…………… 4
English Abstract……..………………………………………………. 6
CHAPTER I --- Introduction……………………………..………….. 11
1. Etiology of oral cancer…………………………………………... 12
2. Immune and oral cancer……………………………………….… 13
3. Lymphocyte population and cancer……………………………... 15
4. CD4+CD3+ T cell, CD8+CD3+ T cell and B cell…………….. 16
5. Natural Killer cell (NK cell)…………………………………….. 17
6. Early and late marker in activation of lymphocytes…………….. 18
7. Chemical carcinogenesis………………………………………... 19
8. Hypothesis………………………………………………..……... 20
CHAPTER II --- Cytotoxicity and transformation of C3H10T1/2 cells induced by areca nut components ……….……….. 22
1. Abstract………………….………………………………….… 22
2. Introduction…………………………………………………… 24
3. Materials and Methods……………………………………..…. 26
4. Results………………………………………………………… 29
5. Discussion…………………………………………………….. 31


CHAPTER III --- Differences in oral habit and lymphocyte subpopulation affect malignant transformation of patients with oral pre-cancer………...……………………………..... 35
1. Abstract………………….………………………………….… 35
2. Introduction…………………………………………………… 37
3. Materials and Methods………………………………………... 40
4. Results………………………………………………………… 42
5. Discussion…………………………………………………….. 44
CHAPTER IV --- Factors affecting the survival of oral cancer patient ………………………………………....... 49
1. Abstract…………………………………………………..…… 49
2. Introduction…………………………………………………… 50
3. Materials and Methods………………………………………... 53
4. Results………………………………………………………… 55
5. Discussion…………………………………………………...... 57
CHAPTER V
1. Conclusion……………….……………………………………. 61
2. References.……………...………………...………….…..…… 65
3. Tables and Figures…..…………………….…………….……. 76




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