系統識別號 U0026-2203201316110600
論文名稱(中文) 新穎的訊號傳遞:Fas Ligand透過Met受體促進細胞移動及腫瘤轉移
論文名稱(英文) A Novel Signaling Pathway for FasL:FasL Hijacks Met receptor to Enhance Cell Motility and Metastasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 林煥晴
研究生(英文) Huan-Ching Lin
學號 s58951413
學位類別 博士
語文別 英文
論文頁數 74頁
口試委員 指導教授-楊倍昌
中文關鍵字 Fas配體  Met受體  細胞爬行  腫瘤轉移 
英文關鍵字 Fas ligand  Met  cell migration  metastasis 
中文摘要 Fas ligand (FasL, CD95L)屬於腫瘤壞死家族一員(Tumor necrosis factor, TNF family),透過結合標的細胞膜上的Fas受體進而誘發計畫性細胞凋亡(programmed cell death, apoptosis),提供毒殺細胞並調控免疫功能。此外, FasL也能藉由在細胞內蛋白片段傳遞相反訊號(reverse signal),進而促進T淋胞細胞增生和活化。除了FasL調控正常的細胞凋亡,許多轉移的腫瘤細胞同樣也表現大量FasL的現象。為了探討FasL表現與腫瘤惡性的關聯,我們實驗室先前建立了表現不同FasL片段的纖維母細胞來進行研究,包含了全長和切除部分功能性片段的FasL。這些大量表現FasL的細胞中,並不會影響細胞的存活率,同時也不會引起內質網壓力(ER Stress)的產生。然而對於細胞移動和侵襲能力卻明顯上升。值得注意的是在一株表現去除細胞內區域FasL的細胞中,在老鼠體內同樣具有很強的轉移能力。在本研究中,我們將深入探討FasL對於腫瘤轉移的訊號與機制。透過免疫沉澱和共軛焦顯微鏡螢光影像的實驗,結果顯示FasL與肝細胞生長因子受體 (Met)在細胞膜脂筏(lipid raft)構造中會結合形成複合體。這複合體會促使肝細胞生長因子受體和下游Stat3分子的活化,這現象與FasL的表現量具有正相關。透過抑制肝細胞生長因子受體和Stat3的活性,能夠有效抑制FasL所引起的細胞移動能力。利用干擾性核醣核酸技術透過降低FasL的表現,也能有效降低FasL所引起的細胞移動能力。這現象在A549、Huh7、PLC/PRF/5、SiHa 和U118等人類的腫瘤細胞可以觀察到。此外,降低肝細胞生長因子受體表現同樣地降低細胞移動能力。我們進一步利用結去不同片段的FasL分析出在細胞外FasL105-130是片段和肝細胞生長因子受體結合的主要片段,透過給予FasL117-126的合成胜肽能夠降低FasL與肝細胞生長因子受體的結合能力,同樣降低細胞移動能力和肝細胞生長因子受體的訊號傳遞。綜合本研究的結果,我們證明FasL在腫瘤細胞中會和肝細胞生長因子受體結合的方式來增加細胞轉移的能力。
英文摘要 Fas ligand (FasL, CD95L) is a well-known critical protein of the tumor necrosis factor (TNF) family that initiates Fas (CD95) engagement and programmed cell death in a variety of susceptible cells to mediate cytotoxicity and immune cell homeostasis. In addition, FasL transmits a reverse signal via the intracellular region to modulate T lymphocyte activation. In addition to normal cells, many late-stage cancer cells also express FasL and show high metastatic potential. Although FasL-related signals can modulate lymphocyte development, the correlation between FasL expression and cancer malignancy is still inconclusive. To verify the uncertain role of FasL intracellular domains, we have previously expressed full-length and deletion variants of human FasL, Δ33 (motif for CK1 binding of the cytoplasmic tail deleted) and Δ70 (motif for CK1 binding and the proline-rich domain deleted) in NIH3T3 cells. Although the ectopic expression of FasL does not induce endoplasmic reticulum (ER) stress or affect cell proliferation and apoptosis, it enhances cell motility and invasion. Truncated FasL, lacking most of the intracellular domain, profoundly enhances lung tumor nodules in nude mice. The present study further investigates FasL-signal-mediated tumor metastasis. The results of confocal imaging and the immunoprecipitation assay obviously show that FasL forms complexes with Met in lipid raft even without the FasL intracellular region and Fas binding sites. In addition, the FasL/Met complexes trigger Met and downstream Stat3 activation that is positively correlated with the levels of FasL expression. The FasL-elevated invasive phenotypes are effectively blocked by Met and Stat3 inhibition. Knocking down the FasL by RNA interference (RNAi) technology appreciably suppresses cell motility of various human cancer cell lines, including A549, Huh7, PLC/PRF/5, SiHa, and U118. In addition, knocking down Met gene expression reverts the FasL-associated motility to the basal level. By diverse truncation FasL constructions, the FasL105-130 extracellular region is identified as the necessary site for FasL interaction with Met in lipid rafts, which consequently leads to Met activation. Furthermore, treatment with a synthetic peptide corresponding to FasL117-126 significantly reduces the FasL/Met interaction, Met pathway activation, and cell motility. Collectively, our results establish the FasL-Met-Stat3 signaling mechanism and explain the metastatic phenotype of FasL-expressing tumors.
論文目次 Abstract...................................................I
Table of Contents..........................................V
List of tables and figures...............................VII
List of Abbreviations...................................VIII
1. Introduction.......................................1
1.1 Fas/FasL interaction...............................1
1.1.1 Fas/FasL interaction for program cell death........1
1.1.2 Negative regulation of Fas signal..................2
1.1.3 Fas/FasL interaction for nonapoptotic regulations..2
1.1.4 FasL-mediated reverse signals......................3
1.1.5 Modulation of FasL.................................4
1.2 FasL and tumor.....................................5
1.2.1 FasL associated tumorigenesis......................5
1.2.2 Fas counterattack mechanism........................5
1.2.3 Mechanisms of tumor resistance to apoptosis........6
1.2.4 Non-apoptotic modulation of FasL in tumor..........8
1.3 Met tyrosine kinase receptor.......................8
1.3.1 Met and hepatocyte growth factor (HGF).............8
1.3.2 Met enhancement of tumor metastasis................9
1.3.3 The cross-talk of Met and other membrane proteins..9
1.3.4 Lipid raft membrane microdomains for signal
2. Study Aim and Experiments Approach Design.........12
3. Materials and Methods.............................13
3.1 Materials.........................................13
3.2 Methods...........................................21
3.2.1 Cell culture......................................21
3.2.2 Suspension cell culture...........................21
3.2.3 FasL construction and bacterial strain store......21
3.2.4 Plasmid DNA Extraction............................22
3.2.5 Lentivirus production.............................22
3.2.6 Flow Cytometry Analysis...........................23
3.2.7 Membrane Protein Extraction.......................23
3.2.8 Western blot analysis.............................24
3.2.9 Immunoprecipitation...............................24
3.2.10 Lipid raft isolation..............................25
3.2.11 Colony formation assay............................25
3.2.12 Single cell motility assay........................26
3.2.13 Flow cytometry assay..............................26
3.2.14 Confocal imaging..................................26
3.2.15 Experimental tumor metastasis in nude mice........27
3.2.16 Gelatin Zymography................................28
3.2.17 Statistical analysis..............................28
4. Results...........................................29
4.1 Expression level of FasL is positively correlated
with cell motility in NIH3T3 and human tumor cell
4.2 FasL-mediated metastasis does not activate
endoplasmic ER stress and MMP production and
4.3 FasL is associated with Met in lipid rafts........31
4.4 FasL activates the Met-Stat3 signaling pathway....33
4.5 FasL/Met interaction through FasL105-130 region...34
4.6 Synthetic short peptides decrease FasL/Met
interaction and cell motility.....................35
4.7 Proposed FasL-Met signaling pathway...............36
5. Discussions.......................................37
5.1 FasL promotes cancer cell motility not through
conventional pathway, Fas and reverse signals.....37
5.2 Cross-talk between Met receptor and other membrane
proteins regulates cell behaviors.................37
5.3 FasL/Met complex potentially promotes epithelial-
mesenchymal transition process in cancer cells....38
5.4 A putative inhibitory signal may be activated by
full-length FasL..................................39
5.5 FasL plays some roles in stem cell formation......39
5.6 The discrepancy of FasL-mediated metastasis may be
caused by different immune response in two
experimental systems..............................40
6. References........................................42
7. Tables............................................55
8. Figures...........................................58
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