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研究生:游欣珊
研究生(外文):Hsin-Shan Yu
論文名稱:瘦體素在人類前列腺癌細胞調節細胞移動及αvβ3Integrin表現的探討
論文名稱(外文):Leptin Mediates Cell Migration and αvβ3 Integrin Up-regulation in Human Prostate Cancer Cells
指導教授:湯智昕
指導教授(外文):Chih-Hsin Tang
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:基礎醫學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:73
中文關鍵詞:瘦體素
外文關鍵詞:LeptinIntegrin
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瘦體素(Leptin)是由肥胖基因所產生的賀爾蒙蛋白並與肥胖有關,藉著新陳代謝的協同作用、飲食行為、能量平衡及神經內分泌的反應來調節體重。此外,瘦體素也被發現存在於許多腫瘤細胞中,並在一些細胞型中表現出促使細胞分裂及血管新生的活性。前列腺癌是男性除了皮膚癌以外最常見的癌症,並且其致死率在全球排名第二。Integrins是哺乳類細胞中主要的黏著因子,並且與癌細胞的轉移有十分密切的相關。在本研究中,我們發現瘦體素會增加人類前列腺癌細胞株(PC3、DU145及LNCaP )的轉移能力及腫瘤細胞(PC3)上αv及β3 integrin的表現。當我們給予前列腺癌細胞Phosphatidylinositol 3-kinase(PI3K)抑制劑(Ly294002)、Akt抑制劑、Nuclear factor-kappaB (NF-κB)抑制劑(PDTC)及IκB protease抑制劑(TPCK)後,從細胞移行實驗(Migration assay)及流式細胞技術分析(Flow cytometric analysis)皆會降低由瘦體素所誘導的移行現象及integrin向上調節(up-regulation)的表現。而將insulin receptor substrate (IRS)-1 small-interference RNA或IKKα, IKKβ, p85及Akt的dominant-negative mutant轉殖入前列腺癌細胞株(PC3)中也能降低瘦體素之作用。而將瘦體素加入前列腺癌細胞株(PC3)後,從西方墨點法分析(Western blot analysis)實驗中可知,瘦體素會刺激IRS-1、PI3K、Akt、 IκB kinase α/β (IKK α/β)、IκBα、p65 Ser536
磷酸化及κB-luciferase活化。此外,我們也在其他前列腺癌細胞株(DU145及LNCaP)中發現了相似的訊號傳遞路徑參予在其中。總和來看,我們的結果發現瘦體素是藉由IRS-1、PI3K、Akt及NF-κB的訊號傳遞路徑,造成αvβ3 integrins的表現增加且造成前列腺癌細胞的轉移
Leptin, the product of the obese gene that is closely associated with obesity and it plays an important role in the regulation of body weight by coordinating metabolism, feeding behavior, energy balance, and neuroendocrine responses. In addition, leptin has been found in many tumor cell lines and has been shown to have mitogenic and angiogenic activity in a number of cell types. Prostate cancer is the most common cancer excluding skin cancer in men and the second leading cause of cancer-related death worldwide. Integrins are the major adhesive molecules in mammalian cells, and has been associated with cancer cells metastasis. In this study, we found that leptin increased the migration and the expression of αvβ3 integrin in human prostate cancer cells (PC3). Leptin-mediated migration and integrin up-regulation was attenuated by PI3K inhibitor (Ly294002), Akt inhibitor, NF-κB inhibitor (PDTC), and IκB protease inhibitor (TPCK). Transfection of cells with insulin receptor substrate (IRS)-1, small-interference RNA or dominant-negative mutant of IKKα, IKKβ, p85 and Akt also inhibited the potentiating action of leptin. Stimulation of PC3 cells with leptin induced IRS-1 phosphorylation, PI3K phosphorylation, IκB kinase α/β (IKK α/β) phosphorylation, IκB phosphorylation, p65 Ser536 phosphorylation, and ĸB-luciferase activity. In addition, we also found that the similar signaling pathways involved in the other prostate cancer cells (DU145 and LNCaP). Taken together, our results suggest that leptin enhances the migration of prostate carcinoma cells by increasing αvβ3 integrin expression through the IRS-1/PI3K/Akt and NF-κB signal transduction pathways.
縮寫表 -----------------------------------------------------------------------------Ⅲ
中文摘要 --------------------------------------------------------------------------Ⅴ
英文摘要 --------------------------------------------------------------------------Ⅷ
第壹章 緒論 --------------------------------------------------------------------01
第一節 前列腺癌 --------------------------------------------------------02
第二節 轉移 --------------------------------------------------------------15
第三節 Integrins ---------------------------------------------------------19
第四節 瘦體素 -----------------------------------------------------------25
第貳章 材料與方法 -----------------------------------------------------------31
第一節 實驗材料 --------------------------------------------------------32
第二節 實驗方法 --------------------------------------------------------33
第三節 統計分析 --------------------------------------------------------36
第參章 結果與討論 -----------------------------------------------------------37
第一節 結果 --------------------------------------------------------------38
第二節 討論 --------------------------------------------------------------43
第肆章 結論 --------------------------------------------------------------------47
參考文獻 --------------------------------------------------------------------------48
圖表 --------------------------------------------------------------------------------54
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