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研究生:洪嘉駿
研究生(外文):Chia-Chun Hung
論文名稱:ACTH突變對POMC抑制黑色素癌與固醇生成之作用
論文名稱(外文):Effects of ACTH Mutations on POMC-induced Melanoma Suppression and Steroidgenesis
指導教授:趙大衛趙大衛引用關係戴明泓
指導教授(外文):David ChaoMing-Hong Tai
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:58
中文關鍵詞:轉移能力腫瘤生長黑色素癌固醇生成基因傳送腺病毒載體壓力荷爾蒙
外文關鍵詞:ACTH (K15A/R17A)metastasisB16-F10H295Rtumor growthsteroidgenesiscorticosteroidsgene deliveryadrenal corticotropin (ACTH)adenovirusProopiomelanocortin (POMC)
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Pro-opiomelanocortin (POMC)是一條241個胺基酸多肽鏈的前軀物,也是一些包括corticotropin (ACTH)、 a-melanocyte-stimulating hormone (a-MSH)、 和b-endorphin (b-EP)的神經性多肽的前軀荷爾蒙。它是一種壓力荷爾蒙,在代謝、能量平衡、和抗發炎反應中都扮演了重要的角色。先前的研究證實,系統性POMC基因傳送透過a-MSH抑制NF-κB/COX2訊息傳遞路徑,對於B16F10黑色素癌細胞不論是活體外(in vitro) 或是活體內(in vivo)的腫瘤生長及轉移能力都有顯著的抑制效果。然而, 系統性POMC基因傳送卻也會引起小鼠的尿量與飲水量的倍增。POMC基因傳送後,使小鼠血漿中的corticosteroids濃度升高及H295R細胞cortisol的產量增加,根據這些證據推測尿量與飲水量倍增可能歸因於固醇生成的增加。Corticosteroids也是強力的抗發炎劑,其所造成的抗發炎反應是否也參與了POMC對腫瘤的抑制,還尚未清楚。為了解開這個謎團,我們製作了包括ACTH (K15A/R17A)在內,一系列帶有不同ACTH突變或是剔除片段的突變型POMC基因的重組腺病毒載體。相較於一般型POMC基因傳送,ACTH (K15A/R17A) 基因傳送在H295R細胞所誘發的cortisol生成量、CYP11B1 mRNA表現量和glucocorticoid responsive element (GRE)-driven luciferase活性皆顯著降低,也不會影響小鼠的尿量和飲水量。而ACTH (K15A/R17A) 基因傳送對於B16F10黑色素癌細胞的腫瘤形成及侵犯能力仍然有顯著的抑制作用。總而言之,在POMC對黑色素癌的抑制作用,固醇生成並非必要存在的因素;此外,ACTH (K15A/R17A) 基因傳送也為黑色素癌的控制提供了更佳的選擇性。
Proopiomelanocortin (POMC) is a 241 amino acids precursor protein, which encodes various neuropeptides including corticotropin (ACTH), a-melanocyte-stimulating hormone (a-MSH), and b-endorphin (b-EP). POMC plays an important role in stress response, metabolism, energy homeostasis and anti-inflammation. Recent studies demonstrated that systemic POMC gene delivery potently suppresses the tumor growth and metastasis of B16-F10 melanoma in vitro and in vivo via inhibition of NF-κB/COX2 pathway. However, systemic POMC expression also led to elevated urine excretion and water intake in mice. This was attributed to enhanced steroidgenesis as evidence by elevated plasma corticosteroids levels in animals and increased cortisol production in adrenal H295R cells after POMC gene delivery. Since corticosteroids are also potent anti-inflammatory agents, it remains unclear whether the ACTH-mediated cortisol synthesis also contributed to the POMC-induced tumor suppression. To address this issue, we generated a series of adenovirus vectors encoding POMC genes with mutation or deletion in ACTH domain including ACTH (K15A/R17A). Unlike the wild type POMC, gene delivery of ACTH (K15A/R17A) resulted in significantly lower cortisol production, CYP11B1 mRNA level, and glucocorticoid responsive element (GRE)-driven luciferase activities in H295R cells. ACTH (K15A/R17A) gene delivery did not affect the urination and water intake in mice. Above all, ACTH (K15A/R17A) gene delivery remained capable of inhibiting the colonies formation and invasiveness of B16-F10 melanoma cells. In summary, steroidgenesis is not essential to POMC-mediated melanoma suppression. In addition, ACTH (K15A/R17A) gene delivery may provide a better alternative for melanoma control.
Abstract in Chinese 4
Abstract in English 5
Abbreviations 6
Introduction 7
Specific Aims 13
Materials and Methods 15
Results 23
Discussion 27
Figures 33
Appendix 50
References 56
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