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研究生:許芝熒
研究生(外文):Chih-Ying Hsu
論文名稱:NF-kB在TNF-a誘導腎臟癌癌化機制角色之探討
論文名稱(外文):The role of Nuclear Factor-kappa B in TNF-a-induced tumorigenesis of renal cell carcinoma.
指導教授:孫光蕙
指導教授(外文):Kuang-Hui Sun
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
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:83
中文關鍵詞:腎臟癌腫瘤壞死因子
外文關鍵詞:TNF-aNF-kBRCC
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Tumor necrosis factor-α (TNF-α) 主要為巨噬細胞所分泌之發炎性細胞激素,負責調控體內發炎反應及免疫細胞之活性;研究發現,高劑量的 TNF-α 會誘發細胞產生凋亡,長時間以低劑量的 TNF-α 處理則會使得癌細胞更加惡化,而 TNF-α 會藉由 NF-κB (Nuclear Factor-kappa B) 之路徑來調控細胞生長等現象; NF-κB為一轉錄因子,其在癌細胞之侵略性、轉移性、抗凋亡、血管新生等現象皆扮演著重要的角色。在本實驗室先前的研究中發現,以 TNF-α 處理低惡性度之腎臟清細胞癌細胞株 (786-O) 後,可觀察到 MMP9 分泌量明顯的上昇,侵略能力也隨之增加,且有 E-Cadherin 表現量下降,Vimentin 表現量上升之 EMT (Epithelial-Mesenchymal-Transition) 現象;因此本篇論文希望探討 NF-κB 在 TNF-α 誘發的腎臟清細胞癌之癌化現象所扮演之角色。
本論文發現在 TNF-α 刺激下,能夠誘使 786-O 細胞由排列緊密規律的上皮細胞型態,轉變成為偏向排列鬆散、呈紡錘狀之間質細胞型態,同時具有較高度的侵略能力。將經過六天的 TNF-α 處理之 786-O 及其對照組打入小鼠皮下,觀察腫瘤生長,也發現經過 TNF-α 處理的組別生長較快;而在不同時間 TNF-α 刺激下會誘導 p65 (RelA) 的磷酸化。因此,我們希望利用抑制 p65 的活化來觀察 NF-κB 是否會對 TNF-α 誘發的腎臟清細胞癌細胞之癌化現象有任何影響。首先利用 NF-κB 抑制劑 Bay11-7082 及 NF-κB Activation Inhibitor 處理細胞,發現皆無法有效的抑制 TNF-α 所誘發的 EMT 現象;為了進一步確認此現象,利用持續活化之 p65,及持續抑制型之 IκBαM 質體轉染 786-O;發現持續活化之 p65 能夠使得 786-O 之 E-Cadherin 表現量部分下降, Vimentin 表現量些微上升,而 TNF-α 處理則有加乘作用,但持續抑制型之 IκBαM 則無法阻斷 TNF-α 所誘發之 EMT 現象;而在 Invasion assay 中發現,持續活化之 p65 能夠促進 786-O 之侵略能力,而 IκBαM 則能夠降低其侵略能力;但不論是持續活化之 p65 或是持續抑制型之 IκBαM 皆不影響 TNF-α 所誘發的 MMP9 表現量上升;另外以 qPCR 確認 MMP2、MMP9、E-cadherin 的 mRNA 表現量皆與蛋白質表現量趨勢一致,而 TNF-脉 也能誘發 EMT 相關之轉錄因子 ZEB-1 之 mRNA 表現量增加,並且 p65 對此現象有些微加乘作用;由以上結果得知,NF-κB 可能部份參與在 TNF-α 誘發 786-O 產生 EMT 現象的路徑中,但並非主要的路徑。
Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine secreted by macrophages that regulates inflammatory responses and immune cells activities. Previous works had demonstrated that high doses of TNF-α induces cell apoptosis, but long-term treatment with low doses of TNF-α enhances the growth of tumor cells, and TNF-α itself acts through the crucial transcription factor NF-κB signaling pathway to regulate tumor cell growth. Our previous studies demonstrated that when renal cell carcinoma cell line 786-O was treated with TNF-α, secretion of MMP9 is significantly increased and accompanied with increased invasion activity. EMT (Epithelial-Mesenchymal-Transition) was also observed with decreased expression of E-cadherin and increased expression of Vimentin. Thus in the present study, the role of NF-κB in TNF-α- induced tumorigenesis of renal cell carcinoma will be examined.
According to our data, TNF-α causes morphological changes in 786-O cells from closely adjoined epithelial cell type to loosely connected, spindle-shaped mesenchymal cell type with increased invasion activity. When TNF-α treated 786-O cells and control 786-O cells were subcutaneously implanted into NOD.CB17-Prkdcscid mice, TNF-α treated cells grow significant faster. We also discovered that TNF-α induces p65 (RelA) phosphorylation in 786-O, so our next step is to identify whether renal cell tumorigenesis can be affected by inhibiting p65 phosphorylation under TNF-α treatment. First we examined the effect of NF-κB inhibitor Bay11-7082 and NF-κB Activation Inhibitor, but EMT induced by TNF-α was unaffected. For further confirmation, 786-O cells were transfected with p65 overexpressing vector and mutant IκBαM overexpressing vector, respectively. Overexpression of p65 slightly decreases E-cadherin expression and increases Vimentin expression, and TNF-α treatment further enhances this effect, but overexpressed mutant IκBαM cannot abolish EMT induced by TNF-α treatment. In invasion assay, overexpression of p65 enhances invasion activity of 786-O cells, while overexpression of mutant IκBαM do the opposite. But both of these two vectors failed to affect MMP9 upregulation induced by TNF-α treatment. Furthermore, qPCR experiments confirmed that MMP2, MMP9 and E-cadherin mRNA were at the same expression level comparing to its protein product, and TNF-α treatment also upregulates other EMT-related transcription factor such as ZEB-1.
According to data listed above, NF-κB may play only a partial role in TNF-α induced EMT in 786-O cells. More works will be done to identify major elements and pathways of this event.
中文摘要................ 2
英文摘要................ 4
一、導論................ 6
二、材料與方法.......... 18
三、結果................ 47
四、討論................ 54
五、參考文獻............ 57
六、結果圖表............ 70
七、附錄................ 80
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