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系統識別號 U0026-2112201113293300
論文名稱(中文) ZBRK1經由調控細胞移動相關基因進而抑制癌症細胞轉移作用之機制探討
論文名稱(英文) Characterization of the mechanisms of ZBRK1 acts as metastasis suppressor through the regulation of cell motility genes
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 100
學期 1
出版年 100
研究生(中文) 林麗芳
研究生(英文) Li-Fang Lin
學號 S5896148
學位類別 博士
語文別 英文
論文頁數 104頁
口試委員 指導教授-王育民
指導教授-張文昌
口試委員-賴明德
口試委員-呂增宏
口試委員-鄭宏祺
口試委員-陳鴻震
口試委員-楊文明
口試委員-洪文俊
中文關鍵字 細胞轉移  腫瘤抑制因子 
英文關鍵字 metastasis  ZBRK1  KAP1  MMP9  tumor suppressor 
學科別分類
中文摘要 癌症的轉移包含許多複雜的過程且為癌症病患主要死因之ㄧ。雖然許多基因已知與促進癌症轉移有關,但是,大多數可抑制癌症轉移的基因仍是未知的。已有文獻指出 BRCA1-interacted transcriptional repressor ZBRK1 會與BRCA1及CtIP形成複合體進而抑制血管生合成因子angiopoietin-1產生,而影響癌化過程中血管新生作用。然而目前仍缺乏證據證明ZBRK1是否可為一腫瘤抑制因子阻斷腫瘤的生成。在本論文中研究發現,ZBRK1在不同子宮頸癌細胞及檢體中表現皆低於正常子宮頸組織。除此之外,ZBRK1具有抑制癌細胞增生及腫瘤生成的能力。藉由利用兩組微陣列分析結果發現,ZBRK1與細胞移動基因的轉錄作用有關。更進一步,發現ZBRK1可藉由抑制調控下游基因MMP9,而具有降低癌症細胞轉移的能力。並且ZBRK1與MMP9表現的正負相關性也在臨床子宮頸癌組織中被偵測。接著,此論文研究也發現ZBRK1可藉由與KAP1或BRCA1結合來調控不同基因表現,故針對KAP1及BRCA1,分別參與ZBRK1在基因調控,癌症轉移的功能性與臨床檢體相關性部份做更深入的探討。結果發現ZBRK1的N端與C端功能區對於ZBRK1抑制癌細胞生長的能力皆具重要性地位。此外,ZBRK1的N端KRAB功能區在ZBRK1抑制癌症轉移的能力上扮演極重要角色。實驗發現ZBRK1可藉由轉錄機制抑制KAP1表現;當ZBRK1表現下降時,KAP1增加且具有促進癌細胞移行的能力。針對此拮抗現象,在臨床不同轉移程度的子宮頸癌檢體中也發現ZBRK1與KAP1的表現存在著負相關性。由此可知ZBRK1的表現下降與KAP1的表現增加加強癌症細胞的轉移能力,可能在癌症細胞的轉移過程亦扮演關鍵性角色。總合以上研究發現,更確立ZBRK1在控制腫瘤生成及抑制癌症轉移上的重要性。
英文摘要 Cancer metastasis comprises multi-complicated steps and is the most common cause of death among cancer patients. Although many genes have revealed associated with cancer metastasis, the genes involved in metastasis prevention remain unclear. Previous study indicated that ZBRK1, the BRCA1-interacted transcriptional repressor, was identified as cooperating with the BRCA1/CtIP to repress angiopoietin-1 gene activation in preventing angiogenesis in tumorigenesis. However, a direct evidence of ZBRK1 as a tumor suppressor has been lacking. In this thesis, we found the expression levels of ZBRK1 in cervical cancer cells and clinical specimens were significantly lower than in normal cervical epithelial tissues. Ectopic expression of ZBRK1 inhibited malignant growth and tumor formation. A coincident result from two microarray profiles revealed that ZBRK1 could inhibit cell movement-related gene transcription. Moreover, ZBRK1 could function as a metastatic suppressor through modulated MMP9 transcription expression and the loss of ZBRK1 expression was inversely correlated with the elevated expression of MMP9 in cervical cancer specimens. Subsequently, the detail molecular mechanism of how BRCA1 and KAP1, the ZBRK1 interaction proteins, participate in ZBRK1-mediated transcriptional repression, metastasis/invasion and their clinical relevance was demonstrated. Both N- and C-termini of ZBRK1 are important in inhibition of proliferation and anchorage-independent activity of cervical cancer cells. In addition, N-terminus KRAB domain of ZBRK1 showed a more crucial role in suppression of metastasis/invasion. Interestingly, several pieces of evidence suggested that ZBRK1 modulated KAP1 function through a transcriptional dependent manner. Loss of ZBRK1 resulted in the increase of KAP1 that enhanced in vitro and in vivo migration and invasion of cervical cancer cells. The study also manifested an opposite correlation between ZBRK1 and KAP1 in the progression from in situ carcinoma to invasive/metastatic cervical cancer specimens. Taken together, loss of ZBRK1 contributes to increase expression of KAP1 that benefits KAP1 serving as a metastatic/invasive enhancer and verifies the significance of ZBRK1 in tumorigenesis and metastasis suppression.
論文目次 Abstract i
中文摘要 iii
致謝 iv
Contents vi
Figure contents ix
Abbreviations xii

Chapter 1. Introduction 1
1-1 Cancer metastasis 1
1-1.1 Gene signatures in cancer metastasis 1
1-1.2 Microarray profiling in searching for metastasis genes 2
1-1.3 Metastasis suppressors in cancer metastasis 3
1-2 Zinc finger protein (ZFP) 4
1-2.1 Krupple-associated box-zinc finger proteins (KRAB-ZFPs) 4
1-2.2 Zinc finger and BRCA1-interacting protein with a KRAB domain-1 (ZBRK1) 6
1-2.3 The role of ZBRK1 in DNA damage response 6
1-2.4 The role of ZBRK1 in tumorigenesis 7
1-2.5 The role of ZBRK1 in cells 8
1-2.5.1 The role of KAP1 in cells 8
1-2.5.2 The role of KAP1 in cancers 9
1-3 Cervical cancer 10
1-3.1 Overview of cervical cancer 10
1-3.2 Matrix metalloproteinases (MMPs) in the progression of cervical cancer 11
1-3.2.1 Matrix metalloproteinases (MMPs) 11
1-3.2.2 Transcriptional regulation of MMPs 12
1-3.2.3 MMPs in cancer 13
1-3.2.4 MMPs in cervical cancer 14
1-4 Specific aims 14

Chapter 2. Materials and methods 16
2-1 Materials 16
2-2 Methods 16
Cell culture and stable cell lines establishment 16
Reporter plasmids and Luciferase assay 17
Reverse transcription Polymerase Chain Reaction (RT-PCR) 17
Microarray analysis 18
Assays for cell proliferation, focus-formation and anchorage-independency 18
Tumor growth analysis in mice 19
Wound healing assay 19
Cell migration and invasion assays 19
Experimental metastasis assay 20
Gelatin zymography 20
Lentiviral shRNA 20
Chromatin immunoprecipitation (ChIP)-PCR assay 21
Patients and tumor specimens 21
Immunohistochemical staining and assessment of ZBRK and KAP1 expression 22
Statistical analysis 22
Chapter 3. Results 24
Expression level of ZBRK1 is attenuated in cervical cancers. 24
ZBRK1 retards cancer cell proliferation, soft-agar colony formation and tumor growth in mice model. 24
ZBRK1 inhibits expression of groups of genes essential for cell proliferation and migration. 25
ZBRK1 inhibits cell migration. 26
ZBRK1 directly regulates the cell metastasis-related gene MMP9. 26
Expression of ZBRK1 is inversely correlated to the expression of MMP9 in cervical cancer specimens. 28
Interactions of ZBRK1 with KAP1 and BRCA1 28
Both N- and C-termini of ZBRK1 are important in the suppression of cancer cell proliferation, but N-terminus of ZBRK1 is critical for the inhibition of cell migration. 29
ZBRK1 represses KAP1 promoter activity. 30
KAP1 level is inversely correlated with the ZBRK1 level in different degree of cervical cancer specimens 32

Chapter 4. Discussion 34
References 44
Figures and legends 54
Appendixes 99
Curriculum vitae 103

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