臺灣博碩士論文加值系統

長久以來，薑黃素廣泛應用在藥物、香料、染劑等使用上。其中在藥物方面，傳統醫學使用薑黃素當作抗發炎藥物。近年來分子醫學研究發現，薑黃素可以抑制與發炎反應相關的轉錄因子：NF-κB，代表薑黃素可能抑制癌症的形成，故薑黃素被視為預防癌症的藥物之一。在前人的研究亦發現薑黃素可以使癌細胞停止生長或是促使癌細胞進入細胞凋亡，但這些機制皆與腫瘤抑制蛋白TP53有關。然而有將近百分之五十的癌症細胞中的TP53是失去活性。本篇研究以人類肝癌細胞Hep3B作為研究對象，觀察薑黃素是否會開啟與TP53非相關的細胞凋亡路徑。結果顯示，薑黃素會使得Hep3B細胞中AKT細胞訊息傳導路徑活性下降且使得JNK 蛋白質表現量上升，這兩條訊息傳導路徑是誘導肝癌細胞進入細胞凋亡的重要關鍵。此外在本篇研究中亦發現，FOXO4可能受到AKT1與JNK的調控。以核酸干擾技術抑制FOXO4之後，發現細胞凋亡的比例下降，同時也降低了Caspase-3和Caspase-8的活性。另外，本研究也討論PPARγ 對於薑黃素所誘發的細胞凋亡路徑中所扮演的角色。從結果得知，以PPARγ的抑制劑阻止薑黃素與PPARγ結合之後，細胞凋亡的比例下降，表示PPARγ在此路徑中可能為中間傳遞者的角色，但在訊息傳遞中的明確地位仍有待釐清。本篇研究發現薑黃素的確可以誘發與TP53無關的細胞凋亡路徑。

Curcumin was used as a remedy agent in Asia area for hundreds years. Recently studies find that curcumin can be used as a chemoprevention agent because it down-regulates NF-κB, a transcriptional factor induces inflammation response. Moreover, curcumin can be used as a therapeutic agent for cancers. Previous studies indicated that curcumin induces cancer cells growth arrest or apoptosis through a p53-dependent pathway. However, nearly 50% of cancers harbor mutant p53 or another mechanism to make p53 loss of function. Hep3B is a p53 null cell line and undergoes apoptosis after treatment with curcumin. Therefore, this study is intent to uncover the p53-independent pathway in Hep3B. Results in this study revealed that curcumin induced apoptotic effect of Hep3B was due to down-regulation of the AKT pathway and activation of the JNK pathway at the same time. FOXO4 is a key regulator in curcumin-induced apoptosis pathway. Knockdown of FOXO4 reduces activities of caspase-8 and caspase-3 and the percentage of subG1 indicates that FOXO4 might be a pro-apoptotic gene. The other factor might affect apoptosis in curcumin-induced apoptosis is PPARγ, a nuclear receptor. Pretreatment with GW9662, the antagonist of PPARγ, reduces the percentage of subG1 as well suggests that PPARγ might be a mediator of the apoptotic pathway induced by curcumin. In conclusion, curcumin can induce Hep3B apoptosis through a p53-independent pathway.

Abstract 1
中文摘要 2 Introduction
3-12
Hepatocellular carcinoma
Polyphenol compounds have therapeutic potential of cancer
Curcumin in chemoprevention and cancer therapy
Apoptosis
The AKT and JNK Pathway
The Forkhead BoxO family
Material and method
13-22
Result 23-28
A. Morphological change
B. Cell cycle analysis
C. Analysis of caspase activity
D. Gene expression microarray analysis
E. Both AKT and JNK pathways were associated with curcumin-induced apoptosis
F. PPARG might be a mediator in curcumin-induced apoptosis event
G. FOXO gene family may be key regulators of curcumin-induced apoptosis
Discussion 29-32
References 33-36
Tables 37-41
Figures 42-61
Appendix 62-65

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