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博碩士論文 etd-0720114-004147 詳細資訊
Title page for etd-0720114-004147
論文名稱
Title
探討Goniothalamin在肝癌細胞株中對蛋白質酶抑制劑的調控機制
Studies on the regulatory mechanisms of GTN-induced protein kinase inhibitors in hepatocellular carcinoma-derived cells
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
67
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2014-07-28
繳交日期
Date of Submission
2014-08-20
關鍵字
Keywords
E3-ligase抑制劑、週期素激酶抑制劑、Goniothalamin (GTN)、CDKN1B、CDKN1C、histone deacetylase抑制劑
E3-ligase inhibitor, HDAC inhibitor, Goniothalamin (GTN), CDKN1B, Cyclin-dependent kinase inhibitors (CKIs), CDKN1C
統計
Statistics
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中文摘要
Goniothalamin (GTN) 為一種styrylpyrone 的衍生物,這類的化合物在先前的許多研究中,已經被發現GTN 對癌細胞具有細胞毒性以及抑制生長的能力。因此在本研究中,我們探討GTN 處理肝癌細胞株後所誘發的週期素激酶抑制劑的調控機制。首先,我們先利用兩株肝癌細胞,TP-53 mutant Huh-7 細胞和TP-53negative Hep-3B 細胞,分別處理GTN 之後,皆會造成細胞週期停滯、聚落生長能力降低以及週期素激酶抑制劑表現量上升等現象。在細胞週期的部分,我們發現兩株細胞在經過GTN 處理之後皆會誘發G0/G1 期的停滯及S 期的減少。為了詳細探討其分子調控機制,我們利用兩株肝癌細胞株觀察所有週期素激酶抑制劑的表現,結果發現,在GTN 處理之後,在Huh-7 細胞中透過抑制SKP2 蛋白表現量進而誘發CDKN1B 蛋白表現,增加CDKN1B 的穩定性並減少蛋白降解,並且利用抑制CCNE1 和CDK2 蛋白表現,導致細胞週期停滯與S 期減少。另外,在Hep-3B 細胞中處理過GTN 後,我們也發現增加了CDKN1C 基因表現量,此機制可能是透過epigenetic modification 誘發並改變組蛋白的表現。我們利用GTN 和trichostatin a (TSA)合併處理Hep-3B 細胞,發現到可以提升histone 3 的乙醯化程度升高。此機制與TSA 的機制相似。總結,根據本研究的結果,我們得知在肝癌細胞株中,GTN 所誘發的細胞週期停滯與細胞凋亡,是透過調控週期素激酶抑制劑的表現;其中在Huh-7 細胞中GTN 扮演E3-ligase抑制劑而誘發CDKN1B 蛋白表現,而在Hep-3B 細胞中則是扮演histone deacetylase抑制劑使CDKN1C 基因表現再活化。
Abstract
The study was to investigate the regulatory mechanisms of goniothalamin (GTN)-induced protein kinase inhibitors, which means cyclin-dependent kinase inhibitors (CKIs), in two hepatocellular carcinoma (HCC)-derived cell lines, Huh-7 and Hep-3B. GTN is a styrylpyrone derivative, is a natural compound with potent cytotoxic and antiporliferative effects for several types of cancer cells. Nonetheless, the detail regulatory mechanisms of GTN in HCC-derived cells have not been investigated before. Results indicated that GTN induced CDKN1B/p27Kip1 protein expression through inhibiting SKP2 protein expression in Huh-7 cells; triggered CDKN1C/p57Kip2 mRNA expression by epigenetic modification in Hep-3B cells. After GTN treatment, SKP2, the specific E3-ligase for CDKN1B in nuclear, was significantly decreasing in protein level but not in mRNA level. This result lead cancer cells to slow down the proliferation and contribute to apoptosis in the Huh-7 cells. Thus, GTN might have the activity of E3-ligase inhibitor in Huh-7 cells. On the other hand, CDKN1C is a tumor suppressor gene in mammalian cells and it might be regulated by epigenetic modification. In Hep-3B cells, the mRNA expression of CDKN1C was induced by GTN, and synergistic increased by trichostatin A (TSA) treatment. We also found the GTN might induce acetylation of histone 3 expression. It suggested the mechanism of GTN might similar to TSA and had a potential inhibition to histone deacetylase (HDAC) in Hep-3B cells. In summary, GTN might represent a novel of anticancer drug that induces CKIs expression in HCC-derived cell lines through plays E3-ligase inhibitor and HDAC inhibitor.
目次 Table of Contents
Approval page i
Acknowledgement ii
Abstract iii
Chinese iii
English iv
Abbreviations v
List of figures vii
List of tables viii
Introduction 1
Materials and Methods 11
Results 22
Figures 31
Discussion 45
References 52
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