臺灣博碩士論文加值系統

2,3-butanediol(2,3-BTD) 是許多細菌從丙酮酸代謝生成的產物。其具有許多生理功能，包含當細菌生長密度太高時扮演調控環境pH值的角色、促進阿拉伯芥的生長和誘導防禦病原菌感染系統的啟動、改善內毒素所誘導的急性肺損傷及抗發炎的效果等。在人體2,3-BTD可因飲酒而產生。因過度攝取酒精是肝癌形成的原因之一，所以我們想探討2,3-BTD是否具有預防肝癌的效果。本研究中，利用化學藥劑所誘導老鼠肝癌模式中，發現2,3-BTD會顯著的改善肝癌病理外觀，並且降低肝臟珈瑪麩胺酸酵素(Gamma-GT)含量，另外也會促進脾臟自然殺手細胞的活性。之前研究顯示，自然殺手細胞對於肝癌的抑制扮演重要的角色，並且與細胞上的活化接受器有關，所以我們利用自然殺手細胞的細胞株NK-92試圖瞭解其被活化的機制。結果發現隨著2,3-BTD濃度提高，導致自然殺手細胞表面上的活化接受器表現亦隨之提高。此外下游的傳遞路徑MAPK及毒殺分子perforin的表現也隨著活化，結果導致自然殺手細胞的毒殺細胞效率提高。2,3-BTD或許是一個預防或治療肝癌的可能化合物。

The compound 2,3-butanediol (2,3-BTD) synthesized in a variety of bacterial species is a metabolite derived from pyruvate. It shows multiple physiological functions, including regulating pH value when bacteria grow to a high cell density, plant systemic resistance against bacterial infection, promoting plant growth, and ameliorating endotoxin-induced acute lung injury in rats. Whether 2,3-BTD shows any effect on anti-tumorigenesis remains unknown. As 2,3-BTD is also synthesized in humans after alcohol uptake and alcoholism is closely related to hepatocellular cancinoma (HCC) formation, in this study, we set out to study whether 2,3-BTD prevents formation of HCC in rats and promotes activity of splenic cytotoxic cells. Results indicated that 2,3-BTD ameliorates chemical-induced HCC formation and activates NK cells activity. The activation mechanism of NK cells is further identified to be mainly through activation of NKG2D and NCR (except NKp30) receptors, and the mitogen-activated protein kinase (MAPK) signaling pathways, especially the JNK and ERK pathway. This subsequently leads to increased expression of perforin and NK cells cytotoxicity. The 2,3-BTD thus shows a potential of being used as an agent in prevention of HCC formation.

指導教授推薦書
口試委員會審定
授權…………………………………………………………………….iii
誌謝………..……………………………………………………………iv
中文摘要.……..………………………………………...........................v
ABSTRACT…...…………………………………...…...........................vi
TABLE OF CONTENTS……,,,,……..…………………..………….…vii
FIGURE AND TABLE CONTENTS……………..……………….........ix
CHAPTER 1 Introduction……………………………………….….….1
1.1 The physiological roles of 2,3-butanediol ………………………..….1
1.2 Hepatocellular carcinoma …………………………………………....1
1.3 Natural killer cells and HCC ………………………………….….….2
1.4 NK cells physiology……………………………………………….…3
1.4.1 Activation and inhibitory receptors of NK cells…………….….3
1.4.2 Signalings and NK cells cytotoxicity…………………………...5
1.4.3 Cytotoxic proteins of NK cells……………………………….…5
1.5 Specific Aims ……………………………………………………..…..6
CHAPTER 2 Materials and Methods…………………………………....7
2.1 Chemical reagents…………………………………………………......7
2.2 HCC rat model …………………………………………………….......7
2.3 Histological examinations ……………………………………….........7
2.4 Analysis of gamma-glutamyl transpeptidase (γ-GT) activity
in liver tissue Sections ……………...…………………………………..…7
2.5 Cell lines and cell culture…………………...………………….….…..8
2.6 Cytotoxicity assay ………………………………………...…….….…8
2.7 RNA extraction and reverse transcription PCR………………………9
2.8 Western blot analysis………………….…………………………….10
CHAPTER 3 Results ………………….…………………………….12
3.1 2,3-BTD prevents HCC formation ………………………………….12
322,3-BTD ameliorates histopathology in experimental
Hepatotumorigenesis…………………………………………….…...12
3.3 2,3-BTD decreases γ-GT activity in liver………………………….....13
3.4 2,3-BTD increases spleen NK cell activities in HCC rats………..…..13
3.5 2,3-BTD activates NK cells activity in vitro……………………..…..13
3.6 2,3-BTD upregulates transcriptional and translation level of NKG2D,
NKp44, NKp46, and perforin…………..…………..…………….14
3.7 2,3-BTD increases phosphorylation of MAPK signaling JNK and ERK
Pathways …………………………………………….…………...…14
CHAPTER 4 Discussion…………………..…………………...………....16
CHAPTER 5 References…………………………………………..……..32
Appendix …………………………………………………………...…….38

FIGURE AND TABLE CONTENTS
Table1 The DNA sequences of primer pairs used in PCR in this study..19
Fig. 1. The signaling pathways from NCRs, CD16 and NKG2D,
through adaptors to MAPKs and virulence protreins in NK cells……..…20
Fig 2. Schematic diagram of the experimental design for induction of
hepatocellular carcinoma…………………………..………………..……21
Fig 3. 2,3-BTD recover DEN/2-AAF/PH induced HCC
formation in rats ……..……………………………………………...……22
Fig 4. Effect of 2,3-BTD on histolopathology change of liver tumors…23
Fig 5. Effect of 2,3-BTD on liver inflammation. This was expressed as γ-GT positive lesion area in liver tumors…………..………………......…24
Fig 6. 2,3-BTD activates spleen NK cells activity in vivo………..….....25
Fig 7A. In vitro activation of NK cells activity by 2,3-BTD………...…26
Fig 7B. Dose-dependent activation of 2,3-BTD on NK cells was
inhibited by JNK inhibitor, SP600125(SP)………………………..……...27
Fig 8A. 2,3-BTD increases mRNA expression of activation receptors and granule proteins in NK cells…….…………………………………..…....28
Fig 8B. 2,3-BTD increases protein expression of activation receptors and cytolytic protein…………………………………………………..……....29
Fig 9A. 2,3-BTD increases phosphorylation of MAPK ERK and JNK
signaling pathways signaling in NK cells…………………………...…....30
Fig 9B. JNK inhibitor, SP600125(SP), suppressed phosphorylation of
JNK signaling pathways signaling in present different concentration of
2,3-BTD in NK cells………………………………………………...……31

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