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研究生:張源清
研究生(外文):Yuan-Ching Chang
論文名稱:瘦體素調節乳癌細胞生長之作用機制
論文名稱(外文):Effect of Leptin on Growth of Breast Cancer Cells
指導教授:張金堅張金堅引用關係
指導教授(外文):King-Jen Chang
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
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:2004
畢業學年度:92
語文別:中文
論文頁數:65
中文關鍵詞:乳癌瘦體素
外文關鍵詞:leptinbreast cancer
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乳癌是女性最普遍的惡性腫瘤之一,為台灣婦女癌症的第二大年發生率,且近十年來,罹患率和死亡率有逐年增加的趨勢。臨床資料發現肥胖與乳癌的發生有極密切的關係,肥胖為乳癌發生之危險因子。脂肪細胞為乳房主要的基質細胞之一,乳腺被豐富之脂肪細胞所包圍,一般認為脂肪細胞會分泌脂肪細胞素調節乳腺細胞生理弁遄A但是何種細胞素目前尚不清楚。瘦體素 (leptin) 為ob(obese) 基因所表現,主要係由脂肪細胞生成,其濃度與體內脂肪含量成正比,負責調控攝食行為及能量代謝,有研究指出,瘦體素和瘦體素受體皆可在正常乳腺細胞及乳癌腫瘤中表現。所以瘦體素可能可以藉由paracrine 和autocrine的機轉來刺激腫瘤細胞增生及分化。利用細胞計數,MTT分析和Brdu incorporation分析,觀察細胞生長情形。發現經瘦體素處理後,乳癌細胞株 (T-47 D 和ZR-75-1) 有明顯細胞增生。以反轉錄聚合鍊反應(RT-PCR)及西方墨點法(Western Blotting Assay)分析特異蛋白質及轉錄因子表現的增減及活化情形。關於細胞週期的調控因子方面,本研究的重要貢獻在於首次發現瘦體素調控了細胞週期中重要進程因子(cyclin D1, p21, p53),增加致癌蛋白(c-Myc)的表現,也增加了抗細胞凋亡因子 (Bcl-2和Bcl-xL)的表現。特別的是瘦體素也可能以藉由endocrine,paracrine 和autocrine的作用機轉,同時促進細胞週期和抑制細胞凋亡,因而刺激乳癌細胞株的增殖。本實驗的結果,將可以提供肥胖何以會促使乳癌之發生及惡化的作用機制以及解釋臨床乳癌治療上何以肥胖患者預後差,又部分患者對於雌性素療法反應不佳,或是經HER-2/neu的人類單株抗體(trastuzumab)藥物治療仍會失敗的原因。若是瘦體素對於乳癌細胞的作用機轉和訊息途徑被更明暸,和其它已知致癌路徑間的交互作用被更清楚研究。可供研發對抗乳癌新療法之標的或是在乳癌預防上重要的著力點。如此,乳癌的治療就能更為完備。
Breast cancer is the most prevalent malignant tumor in women and accounting for leading cause of cancer death among women. Obesity has been recognized as a risk factor for many cancers including breast cancer. The adipocyte represents one of the most abundant cell types surrounding breast cancer cells and the cytokines secreted from adipocytes may prove to be players in a paracrine manner. Leptin is an adipocyte derived cytokine. Leptin and leptin receptors expression has also been detected in normal and tumoral human mammary epithelial cells. Besides the classical function in regulating food intake and body weight, leptin may play a putative role in breast cancer cell growth through an autocrine and paracrine mechanism. By cell counting, MTT assay and Brdu incorporation, we demonstrated cell growth with leptin treatment in ZR-75-1 cells and T-47 D cells. Semiquantitative RT-PCR, Western blotting were use to detect the expression of specific proteins and transcription factors responsible to regulate the cell proliferation. We first found that c-myc, the oncogen from the hell, was upregulated following leptin exposure. We also confirmed theat cyclin D, the possible converge target of oncogenic pathway of estrogen and HER-2/neu, was also upregulated. At the same time, leptin could drive cell cycle progression by downregulation of expression of p53 and p21. Important findings are now emerging that give hope for the development of candidate drug molecules that are directed against a specific oncoprotein. We propose that leptin is a direct stimulating agent in breast cancer growth and play important role in “fail safe mechanism” of breast cancer when treated with antiestrogen and monoclonal antibody to HER-2/neu receptor (trastuzumab). Consequently, the leptin pathway should be further studied as a target for interventions to treat and/or prevent breast cancer.
目錄
頁次
一、中文摘要 7
二、緒論 8
三、研究材料與方法 25
四、結果 28
五、討論 31
六、展望 34
七、英文簡述 35
八、參考文獻36
九、圖表 46
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