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系統識別號 U0026-2007201118204100
論文名稱(中文) 樺木酸經由抑制轉錄因子Sp1調控週期蛋白cyclin A2 表現量而抑制肺癌腫瘤生長
論文名稱(英文) Betulinic Acid Inhibits Lung Cancer Growth via Downregulating Sp1-Mediated Cyclin A2 Expression
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 王玫淳
研究生(英文) Mei-Chung Wang
學號 s26981149
學位類別 碩士
語文別 中文
論文頁數 79頁
口試委員 指導教授-洪建中
口試委員-張文昌
口試委員-劉怡文
中文關鍵字 樺木酸 
英文關鍵字 BA 
學科別分類
中文摘要 肺癌是國人癌症死因中首要因素,五年的存活率僅有15%。目前治療方法以化療、標靶治療為主,但常有藥物阻抗性的現象。雖然中醫發現在天然化合物可用於治療人類疾病上,直到最近幾十年才漸漸了解天然化合物的執行機轉。樺木酸(Betulinic aicd, BA)為五環三萜類化合物,由樺木樹皮萃取而來且具有抗癌活性,並被報導具有選擇專一毒殺癌細胞效果。我們實驗室過去研究指出大部分癌症中,癌細胞會大量表現specific protein 1 (Sp1)。Sp1為轉錄因子,可經由C端的鋅指區域和富含GC區域的促進子進行結合,達到調控基因的轉錄。由於樺木酸在肺癌的研究效果及詳細機轉仍不清楚,因此本研究將探討在樺木酸是否經由影響Sp1及其下游基因的表現,達到抑制肺癌腫瘤的生長。實驗結果發現,在肺癌病人臨床檢體中,免疫組織染色發現Sp1有過度表現的現象,此外,在H1299及A549這兩株人類肺癌細胞中,隨著樺木酸濃度增加,細胞生長被抑制的現象越明顯,Sp1蛋白質表現量也有顯著減少的現象。在異種皮下腫瘤移植中,在背部注射H1299細胞,同時以腹腔注射給予樺木酸,4週後將老鼠犧牲,發現樺木酸處理之下腫瘤體積及重量具有顯著性下降。為了更進一步了解樺木酸對肺腫瘤生長的影響,我們建立使用四環黴素(doxycycline)處理下引發Kras突變的肺癌腫瘤基因轉殖鼠,以樺木酸腹腔注射一至兩個月,相較於餵食四環黴素 5個月癌化的老鼠,在樺木酸處理下,Sp1蛋白質表現量下降,caspase 3被活化,腫瘤也明顯變小。進一步,以腹腔注射光輝霉素(mithramycin A),Sp1抑制劑,我們發現相較於餵食四環黴素 5個月癌化的老鼠,肺腫瘤數目下降。為了找出被Sp1調控的基因,利用從腹腔注射光輝霉素的老鼠取出肺進行Affymatrix microarray分析,在肺腫瘤生成中,有46個和細胞增生相關的基因表現量因為光輝霉素處理而下降,從中選出過去研究已指出和肺癌的預後相關的cyclin A2基因。利用Reporter assay,證實在H1299中過度表現Sp1可使reporter表現上升,當同時給予樺木酸則下降,證實cyclin A2確實為Sp1調控基因。在處理過光輝霉素或樺木酸的肺癌鼠與肺腺癌細胞,cyclin A2的mRNA及蛋白質表現量皆有下降。由於過去報導指出cyclin A2可磷酸化Rb促使細胞週期能夠執行,利用流式細胞儀,探討H1299及A549細胞處理樺木酸 30 µM後,我們發現細胞週期有sub-G1及停滯在G2/M週期的現象。綜合以上結果,我們發現樺木酸可經由抑制Sp1進而影響cyclin A2的活性使細胞有凋亡及停止在G2/M週期,達到抑制肺腫瘤生長的效果。最後,綜合以上發現及先前研究可知,樺木酸可和其他藥物併用成為具有潛力成為癌症治療藥物。
英文摘要 Betulinic acid (BA) was extracted from bark of birch trees and was identified as effect of anticancer. Lung cancer is the leading cause of cancer mortality and the prognosis for lung carcinoma patients is generally poor in Taiwan. The transcription factor, specificity protein (Sp) 1 is overexpressed in several human cancers. The objective of the study is to determine whether BA inhibits lung tumorigenesis through decreasing Sp1 level. In clinically resected lung adenocarcinoma, the level of Sp1 was highly increased. We found that treatment with BA (30 M) inhibited proliferation of H1299 and A549 cells. To confirm the inhibitory effect of BA on lung cancer in vivo, BA was injected intraperitoneally into athymic nude mice containing H1299 cells xenografts and animal were sacrificed after 4 weeks for evaluation of tumor size. There was significantly less tumor size in the BA-treated group compared with the control group. Subsequently, we found that mithramycin A, the Sp1 inhibitor, and BA inhibited lung tumor growth in bitransgenic mice that express constitutively activated Kras4bG12D under the control of doxycycline. In lung tumorigenesis, 46 genes related to cell proliferation possibly regulated by Sp1 were identified by Affymetrix microarray in Kras-induced lung tumor, such as cyclin A2. BA decreased transactivation of cyclin A2 promoter in H1299 cell determined by reporter assay. Previous study has reported that cyclin A2 phosporylates Rb to regulate cell cycle. BA and mithramycin A, repressed mRNA and protein levels of cyclin A2 and Rb in Kras-induced lung tumor mouse and lung adenocarcinoma cells. Flow cytometry revealed that BA induces G2 cell cycle arrest. Based on these finding, BA effectively inhibits lung tumor growth through downregulating Sp1 expression, which directly results in the decrease of cyclin A2. Therefore BA may be a potentially therapeutic drug targeting Sp1 in lung cancer.

論文目次 目錄
中文摘要 ………………………………………………………………………….I
英文摘要 ………………………………………………………………………….III
誌謝………………………………………………………………………………...V
目錄…………………………………………………………………………….......VI
圖目錄……………………………………………………………………………..VIII
表目錄…………………………………………………………………………….. IX
縮寫檢表……………………………………………………………………………X
第一章 序論
第一節 肺癌…………………………………………………………………….1
第二節 肺癌的發生機轉……………………………………………………….1
第三節 樺木酸………………………………………………………………….2
第四節 Sp1……………………………………………………………………...4
第五節 研究動機……………………………………………………………….5
第二章 實驗材料……………………………………………………………………7
第三章 實驗方法…………………………………………………………………...14
第四章 實驗結果
第一節 臨床肺癌病人中Sp1蛋白過度表現…………………………………26
第二節 樺木酸抑制肺腺癌細胞(H1299、A549)生長及減少Sp1蛋白
表現量…………………………………………………………………26
第三節 樺木酸抑制動物體內腫瘤生長……………………………………....27
第四節 樺木酸藉由減少Sp1的表現量而抑制週期蛋白cyclin A2的轉錄與蛋
白質表現…...........................................................................................28
第五節 樺木酸誘發細胞週期停止在G2時期及細胞凋亡…………………29
第五節 結論…………………………………………………………………...29
第五章 實驗討論
第一節 樺木酸使用劑量………………………………………………………30
第二節 pRb蛋白下降對細胞週期的影響…………………………………....30
第三節 樺木酸是否影響其他路徑…………………………………………... 31
第四節 新穎性………………………………………………………................32
參考文獻……………………………………………………………………………33
附圖…………………………………………………………………………………50
附表…………………………………………………………………………………66
附錄…………………………………………………………………………………71
自述…………………………………………………………………………………79




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