檳榔鹼誘導口腔上皮細胞中Cyr61表現之機轉

Yun-Chih Huang; 黃韻芝

請用此 Handle URI 來引用此文件： http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/26787

完整後設資料紀錄

DC 欄位	值	語言
dc.contributor.advisor	郭彥彬(Mark Yen-Ping Kuo)
dc.contributor.author	Yun-Chih Huang	en
dc.contributor.author	黃韻芝	zh_TW
dc.date.accessioned	2021-06-08T07:25:36Z	-
dc.date.copyright	2008-08-13
dc.date.issued	2008
dc.date.submitted	2008-07-15
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dc.identifier.uri	http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/26787	-
dc.description.abstract	根據行政院衛生署民國 95 年統計，口腔癌已成為台灣男性十大癌症發生率的第四位。嚼檳榔已早被證實為導致台灣口腔癌發生最主要的危險因子。檳榔鹼arecoline 是檳榔中最主要的興奮成分，在唾液中的濃度可達 0.9 mM。我們先前發現在口腔癌組織中有較高量的 Cyr61 表現。將過度表現 Cyr61 的口腔癌上皮細胞打入 SCID 鼠會增大腫瘤體積與看到明顯的血管新生。本研究以 0.6 mMarecoline 處理人類牙齦上皮 S-G 細胞株，口腔癌 Ca9-22 細胞株與 KB 細胞株發現都會誘導 Cyr61 蛋白的表現。Cyr61 蛋白在刺激後 4 小時開始上升，12 小時達到高峰，而且 mRNA 的表現也在 0.5 小時開始上升，4 小時達到高峰。並發現0.6 mM arecoline 處理可以誘導含氧自由基（ROS）的產生。加入抗氧化劑N-acetylcysteine (NAC)後可降低 arecoline 誘導的 Cyr61 蛋白表現，說明了在口腔細胞中，arecoline 經由 ROS 而誘導 Cyr61 蛋白的表現。此外，arecoline 也會促使 ras-related small GTPase Rac1 的活化。以 Rac1、P38 MAPK 與 MSK1 之抑制劑(分別為 NSC23766、SB203580 與 H-89)前處理可阻斷 arecoline 誘導的 Cyr61蛋白表現，但是 Rac1 與 p38 MAPK 之抑制劑無法阻斷 arecoline 誘導的 ROS 的產生。西方墨點分析顯示了arecoline 可以活化 CREB。另外 arecoline 亦可以活化 Egr-1 不論是蛋白或是 mRNA 的表現。而加入 AP-1 的抑制劑時也會抑制掉arecoline 對於 Cyr61 的誘導。當細胞加入 HDAC 抑制劑時可加強 arecoline 對於Cyr61 的誘導現象。本研究首次指出arecoline 可誘導口腔細胞Cyr61 蛋白之表現，可能經由 ROS-Rac1-p38-MSK-CREB 訊息傳遞路徑。組蛋白乙醯化(acetylation)也在 arecoline 對 Cyr61 誘導的過程中扮演了重要的角色。另外Ｅgr-1 與 AP-1 在其中所扮演的角色有待更進一步的證實。冀望未來可以藉由抑制這些訊息傳遞路徑成員來達到抑制嚼食檳榔導致的口腔癌。	zh_TW
dc.description.abstract	According to the 2006 census of department of health, Executive Yuan, ROC, oral cancer ranks fourth in the mortality rate of male cancer patient in Taiwan. Areca chewing has been affirmed as the major risk factor of oral caner. Arecoline is the major ingredient of areca nut and the concentration can reach 0.9 mM in saliva. Recent studies show that Cyr61 is expressed at high level in oral cancer. Cyr61-expressed clones could promote in vivo tumor formation and angiogenesis in SCID mice. We identify 0.6mM arecoline can induce the expression of Cyr61 in oral epithelial cell SG, Ca9-22 and KB lines. Arecoline also can induce generation of ROS . ROS inhibitor, N-acetylcysteine can inhibite the expression of Cyr61 in KB cell. Arecoline can activate ras-related small GTPase Rac1. Rac1 inhibitor, NSC23766 and p38 MAPK inhibitor, SB203580 and MSK1 inhibitor, H89 also inhibited the expression of Cyr61 induced by arecoline whereas NSC23766 and SB203580 did not inhibit the generation of ROS. Western blotting showed that arecoline activated CREB. Arecoline also induced the expression of Egr-1. Furthermore, curcumin, an AP-1inhibitor, inhibited the arecoline-induced Cyr61 expression. Thus, arecoline may induce the expression of Cyr61 through ROS-Rac1-p38 MAPK-MSK-CREB signaling pathway. HDAC inhibitor, SAHA or TSA increased the induction of Cyr61 by arecoline. Histone acetylation may play an important role in the expression of Cyr61 induced by arecoline. Blocking the arecoline-induced Cyr61 signaling may provide an alternative therapeutic approach for the treatment of oral cancer in Taiwan.	en
dc.description.provenance	Made available in DSpace on 2021-06-08T07:25:36Z (GMT). No. of bitstreams: 1 ntu-97-R95450010-1.pdf: 5648066 bytes, checksum: bf0b894598d34d1a695e5046a68562c8 (MD5) Previous issue date: 2008	en
dc.description.tableofcontents	中文摘要 ...................................................................1 Abstract ......................................................................2 導論 ...........................................................................3 第一節口腔癌...........................................................3 1-1 口腔癌的流行病學 .............................................3 1-2 口腔癌的病理學 .................................................3 1-3 口腔癌的治療 ....................................................3 1-4 口腔癌的危險因子 .............................................4 第二節 Cyr61 (Cysteine-rich protein) ........................7 2-1 Cyr61 的簡介 ..................................................... 7 2-2 Cyr61 在癌症中所扮演的角色 .......................... 8 2-3 Cyr61 訊息傳導及基因調控 .............................. 11 實驗目的 ....................................................................14 實驗材料與方法 ........................................................ 15 第一節細胞株與細胞培養......................................... 15 第二節藥物的處理..................................................... 15 第三節西方墨點法......................................................17 第四節 RNA 的萃取 ....................................................19 第五節 RNA 的反轉錄 ................................................20 第六節 Real-Time PCR .................................................21 第七節利用 Flow cytometry 作活性氧自由基的測定 ............. 22 第八節 Rac1 activity assay ..........................................22 結果 ............................................................................. 24 檳榔鹼 arecoline 可以誘導口腔上皮細胞中 Cyr61 蛋白的表現 ..................... 24 Arecoline 會誘導 KB 細胞株中 Cyr61 mRNA 的表現 ..................................... 24 Arecoline 並非經由活化蕈菇膽鹼接受器(muscarinic acetylcholine receptors) 來誘導口腔癌 KB 細胞株中 Cyr61 表現 .......................................................... 25 ROS 抑制劑與 p38 抑制劑會抑制 arecoline 對於 Cyr61 的誘導 .................. 25 Arecoline 會誘導 KB 細胞株中 ROS 的產生 ................................................... 25 Ras-related Small GTPase Rac1 參與 arecoline 誘導 Cyr61 ............................ 26 Arecoline 可活化 Rac1 ....................................................................................... 27 Arecoline 會促進 p38 MAPK phosphorylation .................................................. 27 Arecoline 會促進 CREB phosphorylation .......................................................... 28 Arecoline 可能經過 Rac1/p38 MAPK/MSK1 訊息傳遞路徑誘導 Cyr61 表現 ........................................... 28 Egr-1 與 AP-1 可能參與在 arecoline 誘導 Cyr61 基因的調控 ........................ 29 加入 HDAC inhibitor 會加強 arecoline 對於 Cyr61 的誘導現象 ..................... 29 討論 ................................................................ 31 圖與表 .............................................................35 Reference ........................................................ 66
dc.language.iso	zh-TW
dc.subject	檳榔鹼	zh_TW
dc.subject	Cyr61	en
dc.title	檳榔鹼誘導口腔上皮細胞中Cyr61表現之機轉	zh_TW
dc.title	Arecoline induces Cyr61 expression in oral epithelial cells	en
dc.type	Thesis
dc.date.schoolyear	96-2
dc.description.degree	碩士
dc.contributor.oralexamcommittee	蕭宏昇,周涵怡
dc.subject.keyword	檳榔鹼,	zh_TW
dc.subject.keyword	Cyr61,	en
dc.relation.page	72
dc.rights.note	未授權
dc.date.accepted	2008-07-16
dc.contributor.author-college	醫學院	zh_TW
dc.contributor.author-dept	口腔生物科學研究所	zh_TW
顯示於系所單位：	口腔生物科學研究所

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