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系統識別號 U0026-1508201315005000
論文名稱(中文) 腫瘤抑制子WWOX在細胞間的識別與細胞移行中扮演重要的角色
論文名稱(英文) Tumor suppressor WWOX plays a crucial role in cell-to-cell recognition and cell migration
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 陳俞安
研究生(英文) Yu-An Chen
學號 T16001037
學位類別 碩士
語文別 英文
論文頁數 103頁
口試委員 指導教授-張南山
口試委員-賴明德
口試委員-林以行
口試委員-劉校生
口試委員-徐麗君
中文關鍵字 含雙色胺酸功能區氧化還原酶 (WWOX/ WOX1)  WWgre  SDRrepl  反向移行(retrograde) 
英文關鍵字 WWOX  WWgre  SDRrepl  retrograde 
學科別分類
中文摘要 在許多轉移癌細胞中,腫瘤抑制子WWOX往往是缺失的。先前研究已證明,有一部分的WWOX的確會表現在細胞膜以及細胞骨架的區域,並且參與細胞外刺激訊號的傳遞。藉由況時攝影顯微鏡,我們證實WWOX在細胞移行以及細胞間的識別扮演著相當重要的角色。Wwox基因剔除的老鼠胚胎纖維母細胞(Wwox-/- MEF cells)以單顆細胞獨立移行的模式為主,而野生型Wwox基因表現的老鼠胚胎纖維母細胞(Wwox+/+ MEF cells),其移行則呈現群聚一起向前的模式。有趣地是,當Wwox-/- MEF cells遇到Wwox+/+ MEF cells,他們無法辨識彼此,並且Wwox-/- MEF cells 會藉由伸長偽足試探Wwox+/+ MEF cells,且快速地往回跑,並迅速分裂。而此現象也可在其他許多WWOX 缺失的細胞遇上WWOX表現的細胞時發現。進一步地分析,我們發現,WWOX N 端的一個小片段,WWgre(WOX1 7-21),會促進細胞移行的能力,吸引前來的細胞。相反地,WWOX C 端的一個小片段,SDRrepl(WOX1 286-299) 則會抑制細胞的移行,擊退前來的細胞。我們利用螢光共振能量轉換分析,證明WWOX可以藉由自身的WW domain 或是SDR domain的交互作用,或是domain自己的結合來進行結構上的轉換。或許,惡性的轉移癌細胞就是藉著降低自身WWOX的表現,使得原位表現WWOX的腫瘤細胞無法辨識它,進而排斥它而促進轉移的效果。因此,釐清WWOX在細胞移行以及細胞間識別上的調控機轉,將提供一個相當具有潛力的治療策略。
英文摘要 Tumor suppressor WWOX is frequently deficient in metastatic cancer cells. Despite its lacking of nuclear localization signal, WWOX is anchored, in part, at the cell membrane/cytoskeleton area and is able to sense alterations of extracellular cues. By time-lapse microscopy, we determined that WWOX plays an important role in cell migration and cell-to-cell recognition. Wwox-/- MEF cells migrated individually, however, wild type Wwox+/+ MEF cells migrated collectively. Remarkably, when wild type Wwox+/+ MEF cells met Wwox-/- MEF cells, they failed to recognize each other, the knockout cells stretched out with their pseudopodia to touch the wild type cells, and then move in a retrograde manner, followed by dividing immediately. The phenomena could be observed in many WWOX-deficient cells upon encounteringWWOX-positive cells. Molecular analysis also revealed that when cells overexpressing WWgre (WOX1 7-21), a short N-terminal segment of WWOX, they attracted visiting cells. In contrast, if they overexpressed SDRrepl (WOX1 286-299), a short segment in the C-terminal SDR domain, they repelled the visiting cells. Specific antibodies against SDRrepl or WWgre blocked the WWOX-regulated cell recognition effects. FRET analysis showed that upon activation, WWOX may undergo conformational changes, thus leading to inter- or intra-molecular interactions via WW and/or SDR domain interaction or self-binding. Accordingly, under the pressure of metastasis, surface WWOX disappears from cancer cells. These cells are no longer recognized by the parental cancer cells, and thus repelled from the cancer mass. These repulsed cells look for WWOX-negative sites in organs for docking and homing.
論文目次 中文摘要 I
Abstract II
致謝 III
Table of Contents IV
Index of Figures VI
Abbreviation VIII
Introduction 1
WW domain-containing oxidoreductase WWOX/WOX1 1
WWOX suppresses tumorigenesity 3
Down-regulation of WWOX in cancer cells 6
WWOX is not just a tumor suppressor 7
TGFβ signaling pathway and cancer progression 9
Cell migration and cancer metastasis 11
The purpose of this study 15
Materials and Methods 16
Cell lines and cell culture 16
Stable transfectants 17
cDNA constructs and electroporation 18
Chemicals and antibodies 18
Synthetic peptides and antibodies 19
Cell migration assay and time-lapse microscopy 20
Immunofluorescent staining 21
Confocal Microscopy 22
Immunohistochemistry staining 22
Förster (Fluorescence) Resonance Energy Transfer (FRET) 23
Cell cycle analysis 24
Soft agarose colony formation assay 24
2D invasion assay 24
Transwell invasion assay 25
Animal experiment 26
Statistical analysis 26
Results 27
Tumor suppressor WWOX in cell migration and cell-to-cell recognition 27
Molecular dissection of WWOX: two faces of WWOX in cell migration and cell-to-cell recognition 29
SDRrepl antibodies abolish SDRrepl function, and alter cell retrograde migration 31
TGFβ1 induces WWOX and TGF-β type II receptor (TβRII) to relocate into cytoplasm and alters WWOX-mediated cell-to-cell recognition 34
Conformational alteration of WWOX may play a role in cell-to-cell recognition 36
SDRrepl and TGFβ participate in the regulation of cell invasion 36
WWOX inhibits anchorage-independent cell growth of MDA-MB-231 breast cancer cells 37
WWOX regulates cancer cells metastasis in vivo 38
Discussions 40
References 46
Figures 55
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