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研究生:蔡易珊
研究生(外文):Yi-Shan Tsai
論文名稱:檳榔鹼主要成份arecoline對人類表皮細胞之致癌機轉的探討
論文名稱(外文):The carcinogenic role of arecoline in human epithelial cells
指導教授:鐘育志鐘育志引用關係
指導教授(外文):Yuh-Jyh Jong
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:135
中文關鍵詞:檳榔檳榔素DNA損害DNA 修復p53人類上表皮細胞
外文關鍵詞:areca nutarecolineDNA damage responseDNA repairp53human epithelial cells
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世界衛生組織國際癌症研究中心(IARC)在2004年公告檳榔是一級致癌物,且嚼食檳榔跟罹患口腔癌有高度相關。在台灣約有超過兩百萬嚼食檳榔者,檳榔對於口腔所造成的病理病兆已經被確立了,但是檳榔對於口腔的致癌分子機轉尚未被明顯地探討。在我們的研究中發現檳榔的主要成分檳榔素(arecoline) 透過抑制p53進一步抑制 DNA修復。我們利用??-H2AX的磷酸化現象,證實它造成DNA的損害。並且也證實檳榔素在KB、HEp-2 與293 細胞中處理24小時內均發現檳榔素啟動細胞DNA損害的訊息傳遞路徑,透過ATM、NBS1、Chk1、Chk2、p53和Cdc25C的磷酸化,導致細胞最後G2/M時期的停滯。同時我們也發現在紫外光照射後 DNA 的修復,在有檳榔素的存在下會明顯受到抑制。而且,p53的表現與其轉錄活性也明顯受到抑制。在分析臨床檢體有嚼食檳榔病人的口腔腫瘤組織發現p53 mRNA表現也是被抑制。因此本研究證實檳榔素造成的口腔上皮細胞的癌化機轉是透過抑制p53與p53參與的DNA修復所致。
The International Agency for Research on Cancer (IARC) declared that areca nut was carcinogenic to human. Areca nut is the main component of betel quid (BQ), which is commonly consumed in Asia. Epidemiological studies have shown that BQ chewing is a predominant risk factor for oral and pharyngeal cancers. It has been known that areca nut is genotoxic to human epithelial cells. However, the molecular and cellular mechanisms underlying areca nut-associated genotoxicity are not fully understood. Here we showed that arecoline, a major alkaloid of areca nut, might contribute to oral carcinogenesis through inhibiting p53 and DNA repair. We found, on the biological aspect, that arecoline could induce ??-H2AX phosphorylation, a sensitive DNA damage marker, in KB, HEp-2, and 293 cells, suggesting that DNA damages were elicited by arecoline. This phenomenon was supported by the observations of arecoline-induced hyperphosphorylation of ATM, Nbs1, Chk1/2, p53, and Cdc25C, as well as G2/M cell cycle arrest, indicating that a cellular DNA damage response was activated. To explore the possible mechanism accounting for arecoline-elicited DNA damages, we found that arecoline could inhibit p53 by its expression and transactivation function. As a result, the expression of p53-regulated p21WAF1 and the p53-activated DNA repair were repressed by arecoline. Finally, we showed that p53 mRNA transcriptswere frequently downregulated in BQ-associated oral cancer, suggesting that arecoline-mediated p53 inhibition might play a role in BQ-associated tumorigenesis.
中文摘要………………………………………………………4
英文摘要………………………………………………………5
縮寫表…………………………………………………………6
第一章 緒論
第一節頭頸部癌的分子病理概況…………………………………… 8
第二節檳榔為一級致癌物…………………………………………… 9
第三節DNA損害和DNA修補與癌症生成之關係…………………14
第四節p53 蛋白在DNA 損害修補機制的角色……………………24
第五節細胞有絲分裂與腫瘤的關係………………………………….32
第六節研究方向與目的……………………………………………….39
第七節研究材料與試劑……………………………………………… 41
第二章 檳榔素(arecoline)如何對細胞產生毒害(DNA damage)與細胞修復(repair)的分子機轉
第一節 序言……………………………………………………………47
第二節 研究方法………………………………………………………49
第三節 結果……………………………………………………………55
第四節 圖表……………………………………………………………60
第五節 討論……………………………………………………………71
第六節 參考文獻………………………………………………………73
第三章 檳榔素(arecoline)對細胞週期中有絲分裂激素(mitotic kinases)的影響
第一節 序言……………………………………………………………90
第二節 研究方法………………………………………………………93
第三節 結果………………………………………………………….102
第四節 圖表………………………………………………………….106
第五節 討論………………………………………………………….117
第六節 參考文獻…………………………………………………… 121
第四章 總結………………………………………………………..127
附錄:
同意臨床試驗證明書…………………………………………134
論文發表…………………………………………………………..135
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