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研究生:陳俐如
研究生(外文):Li Ju Chen
論文名稱:尼古丁對口腔黏膜細胞在形態與基因表現影響之分析
論文名稱(外文):Phenotype characterization and transcriptome profiling of oral mucosa cells chronically exposed to nicotine
指導教授:鄭恩加
指導教授(外文):A. J. Cheng
學位類別:碩士
校院名稱:長庚大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:87
中文關鍵詞:尼古丁口腔癌
外文關鍵詞:nicotineoral cancer
相關次數:
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口腔癌是全球好發癌症的第六位,且每年有超過500,000個新病例被診斷出來。在過去文獻中指出,長期暴露在危險因子下的人會有較高的比例導致口腔癌的發生,例如抽菸者。此外有研究發現80%以上的口腔癌病人曾經有抽菸習慣使用菸草製品,其口腔癌的發生率高於沒有抽菸的人約5~7倍。在香菸裡最主要的成分是尼古丁,然而尼古丁是否造成口腔癌的發生及如何影響其發展仍然不清楚,更是本論文研究的目的。本研究以模擬現實環境,以濃度70%致死劑量(IC70)的尼古丁慢性處理細胞3個月,由此建立出六株尼古丁處理子代細胞。實驗結果中發現,尼古丁處理子代細胞具有較高的尼古丁耐受度,在不同的細胞株中比起母代細胞增加1.2至2.1倍。同時也發現經尼古丁長期處理的子代細胞具有較高的cisplatin抗性,然而對於放射線的抗性則沒有明顯的差異。另外,在長期處理尼古丁的過程中,我們也觀察到其子代細胞的生長會受到抑制,但隨著處理時間增加,抑制現象也隨之緩解。除此之外,尼古丁處理之子代細胞不論在侵犯或轉移的能力都明顯的增加,而經初步實驗認為此能力增加可能是經由上皮間質轉化所導致。這些尼古丁引起的表現型改變都印證了在臨床上具抽菸習慣病人容易有較高的化療藥物抗性且其癌症具高轉移性的特性。進一步利用cDNA microarray的方式,全盤性的分析這些細胞株基因表現變化,初步發現改變的基因參與各種不同的生物機制如免疫反應、細胞貼附、發育和訊息傳遞。我們更進一步以real-time PCR對基因表現作確認,找到在各細胞株中變化較一致的4個候選基因,即SPARC,SERP1,ANPEP及CCL20。事實上,這些基因在過去曾被報導在癌症發展中扮演重要的角色,然而對於其在口腔癌化中的詳細機制則需進一步作研究。本研究專題對於尼古丁處理所導致細胞表現型和基因型的改變,將可提供一些線索去了解尼古丁如何影響口腔癌的發展。
Oral cancer (ORC) is the sixth most frequent cancer in the world with an estimated over 500,000 new cases being diagnosed annually. Oral cancer is characterized as prolonged exposure to potential risk factors, including cigarette smoking. Worldwide, approximately 80% of ORC patients have smoked or used tobacco products; and these patients are estimated with 5~7 times greater risk of developing cancer than nonsmokers. Nicotine is the most important active tobacco component. How the nicotine affects cell phenotype leading to cancer development is largely unknown. To elucidate the molecular basis of nicotine induced oral carcinogenesis and mimic clinical situation, we have established 6 sublines of oral mucosa cells, by chronic treatment with nicotine at the IC70 dose for 3 months. Results of these sublines showed higher tolerance to further nicotine treatment, with 1.2 to 2.1 fold of increase in various cell lines. Although no significant difference in radiosensitivity, these sublines exhibited higher resistance in cisplatin treatment, with approximately averaged 1.6 folds more of resistance in all cell lines. These results may imply the potential chemoresistance in the cisplatin treating ORC patients with smoking habit. As for cell growth, these nicotine-trained sublines also showed a transiently slow down in the first month but back to the same rate with the parent cells after 3 months. More significantly, the invasion and migration abilities were increased with the treatment time in all lines of cells. At the end of 3 month, the invasion ability increased to 2 to 7.5 folds among the sublines. These phenotypic alterations were accompanying with epithelial-mesenchymal transition (EMT) as indicated by the specific marker alterations. cDNA microarray was used to compare the transcriptomes between the parental and sublines. Heretical cluster and algorithmic analyses of the microarray dataset revealed that several functional pathways might associate with these phenotypic alterations. Results of this study provide cellular and molecular knowledge in the cigarette associated oral carcinogenesis.

Table of Contents

Background and Significance………………………………………....-1-
Oral cancer…………………………………………….…………-1-
Association of carcinogen exposure with oral cancer……..……..-2-
Nicotine…...………………………………………………….…..-4-
Chemical properties of nicotine .……………………….…...-4-
Absorption of nicotine…………………………….…….…...-5-
Nicotinic acetylcholine receptors (nAChR)…………….…...-6-
The biological effects of nicotine……………………...…………-8-
The effects of nicotine on oxidative stress…………………..-8-
The effects of nicotine on apoptosis………………...……...-10-
The effects of nicotine on cell proliferation……………......-11-
Genotoxic potentials of nicotine………………….………..-13-
Effects of nicotine on gene expression………..…………. ..-14-
The effects of nicotine on cell metastasis…………….…....-15-
Specific Aims……………………………………….………….-18-
Material and methods.…….………………...……………………….-19-
Results……………………………………….…….………………….-24-
Discussion………………………….……………….…………………-32-
References………………………………………….…………………-38-
Table and Figure………………………………….….……………….-56-
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