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系統識別號 U0026-3107201213274500
論文名稱(中文) 凝血酶調節素在巨噬細胞移行及腫瘤生長所扮演的角色
論文名稱(英文) The Role of Thrombomodulin in Macrophage Migration and Tumor Growth
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 100
學期 2
出版年 101
研究生(中文) 鍾佩蓉
研究生(英文) Pei-Rong Chung
學號 s16991053
學位類別 碩士
語文別 英文
論文頁數 83頁
口試委員 指導教授-吳華林
口試委員-施桂月
口試委員-林淑華
口試委員-蔡曜聲
中文關鍵字 凝血酶調節素  巨噬細胞 
英文關鍵字 thrombomodulin  macrophage 
學科別分類
中文摘要 凝血酶調節素是一個具有抗凝血功能的穿膜蛋白,在內皮細胞、角質細胞、嗜中性白血球、單核球細胞以及巨噬細胞都有表現。過去的研究指出凝血酶調節素不只具有抗凝血作用,也參與其它生理調控,例如細胞間的黏附、發炎反應、血管新生以及腫瘤生長的過程。巨噬細胞主要可以活化成兩種型態,典型活化的巨噬細胞(或稱M1巨噬細胞)與另類活化的巨噬細胞(或稱M2巨噬細胞)。M1巨噬細胞會表現較高的發炎細胞激素,而M2巨噬細胞則高度表現巨噬細胞甘露醣受體與介質白素-10。巨噬細胞能夠浸潤至腫瘤中並且分泌血管新生因子促進腫瘤生長。過去的文獻指出單核球細胞及巨噬細胞能表現凝血酶調節素,然而對於單核球細胞中的凝血酶調節素的功能仍不清楚。在此次的研究中,我們利用特定在髓細胞剔除凝血酶調節素的小鼠來研究在單核球細胞中的凝血酶調節素在腫瘤生長時所扮演的角色。研究結果顯示黑色素瘤的腫瘤體積及腫瘤重量在髓細胞剔除凝血酶調節素的小鼠中有增加的趨勢,並且巨噬細胞浸潤至黑色素瘤的數量也增加;而缺乏凝血酶調節素的巨噬細胞具有較高的巨噬細胞群落刺激因子受體及CC趨化因子受體2的表現,能夠引起與巨噬細胞爬行相關的訊息傳遞途徑活化,包括細胞外訊號調節激酶1/2、Akt2、Cdc42。此外,缺乏凝血酶調節素的巨噬細胞能高度表現巨噬細胞甘露醣受體與介質白素-10,顯示缺乏凝血酶調節素的巨噬細胞具有M2巨噬細胞的特徵。綜合以上結果,我們證明凝血酶調節素能調控巨噬細胞的化學趨性能力,進而增加巨噬細胞浸潤至黑色素瘤的數量,促進黑色素瘤的生長。
英文摘要 Thrombomodulin (TM), a well-characterized anticoagulant protein, is expressed in many cell types, including endothelial cells, keratinocytes, neutrophils, monocytes, and macrophages. Recent studies have reported that TM not only regulates haemostasis but also is involved in other biological processes such as cell-cell adhesion, inflammation, angiogenesis, and tumor progression. Increasing evidence indicates that macrophages can be polarized into two main phenotypes: classically activated macrophages (or M1 macrophages) and alternatively activated macrophages (or M2 macrophages). M1 macrophages favor to express inflammatory cytokines, and M2 macrophages highly express macrophage mannose receptor (MMR) and interleukin (IL)-10. It has been demonstrated that macrophages can infiltrate into tumors and promote tumor growth by secreting angiogenic factors. Although TM expression has been found, the function of monocytic TM is still poorly understood. In this study, we used the myeloid-specific TM-deficient mice (LysMcre/TMflox/flox mice) to investigate the role of monocytic TM in tumor growth. The results showed that melanoma tumor volume and tumor weight were increased in LysMcre/TMflox/flox mice, and the number of infiltrated macrophages in the tumor of LysMcre/TMflox/flox mice was also increased. In addition, the elevation of migration-related signaling pathways in TM-deficient macrophages, including extracellular signal-regulated kinase (ERK) 1/2, Akt2, and Cdc42, was caused by the up-regulated expression of macrophage colony-stimulating factor receptor (MCSFR) and CC chemokine receptor 2 (CCR2). Furthermore, the expression of MMR and IL-10 was also enhanced in TM-deficient macrophages, indicating that TM-deficient macrophages may display M2-like phenotype. In conclusion, we demonstrate that TM regulates macrophage chemotaxis and loss of monocytic TM in mice promotes melanoma tumor growth by the increase in macrophage infiltration.
論文目次 1.中文摘要 1
2.Abstract 2
3.Acknowledgement 4
4.Contents 6
5.List of Figures 9
6.List of Appendixes 10
7.Abbreviation 11
8.Introduction 13
9.Objective of this study 21
10.Materials and Methods 22
1. Cell Culture
1.1 Mouse peritoneal macrophages
1.2 Bone marrow-derived macrophages (BMDMs)
1.3 Murine melanoma tumor cell line, B16F10
1.3.1 Subcultivation
1.3.2 Cell freezing
1.3.3 Cell thawing
1.4 Cell counting

2. Ribonucleic acid (RNA) extraction and reverse transcription polymerase chain reaction (RT-PCR)
2.1 RNA extraction
2.2 RT-PCR
2.3 Agarose gel electrophoresis

3. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting
3.1 Protein sample preparation
3.2 Protein sample quantification
3.3 SDS-PAGE electrophoresis
3.3.1 Polyacrylamide gel preparation
3.3.2 SDS-PAGE electrophoresis
3.4 Western blotting

4. Generation of the myeloid-specific TM-deficient mice (LysMcre/TMflox/flox mice)
5. Measurement of melanoma tumor growth in mice
6. Chemotaxis assay

7. Flow cytometry
7.1 The number of infiltrated macrophages in tumor
7.2 The expression of chemokine receptors

8. Enzyme-linked immunosorbent assay (ELISA)
9. Statistical Analysis
11. Results 54
Ⅰ. Establishment of the myeloid-specific TM-deficient mice
(LysMcre/TMflox/flox mice)
Ⅱ. Melanoma tumor growth is enhanced in LysMcre/TMflox/flox mice
Ⅲ. Loss of TM in macrophages results in the increased chemotactic ability in vivo and in vitro
Ⅳ. TM-deficient macrophages display elevated migration-related signals
Ⅴ. The expression of chemokine receptors is up-regulated in TM-deficient
macrophages
Ⅵ. Increased expression of MMR and IL-10 is observed in TM-deficient
macrophages

12.Discussion 60
13.References 65
14.Figures 75
15.Appendixes 81
16.Author’s Resume 83
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