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系統識別號 U0026-0704201412165600
論文名稱(中文) 探討EMP2及EMP3基因在人類尿路上皮癌之角色
論文名稱(英文) The significance of EMP2 and EMP3 genes on human urothelial cacinoma
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 102
學期 2
出版年 103
研究生(中文) 王怡文
研究生(英文) Yi-Wen Wang
學號 S58941117
學位類別 博士
語文別 英文
論文頁數 100頁
口試委員 指導教授-周楠華
召集委員-賴明德
口試委員-劉校生
口試委員-凌斌
口試委員-吳文正
口試委員-薛佑玲
中文關鍵字 上尿路上皮癌  大豆異黃酮  上皮膜蛋白  上皮膜蛋白2  抑癌基因  整合素  上皮膜蛋白3  致癌基因  人類表皮生長因子受體2 
英文關鍵字 upper urinary tract urothelial carcinoma (UUT-UC)  isoflavones  epithelial membrane protein  EMP2  tumor suppressor gene  integrin  EMP3  oncogene  ErbB2 
學科別分類
中文摘要 癌症是台灣近30年來造成死亡的重要影響因素。90-95% 的尿路上皮癌發生在膀胱,5-10% 發生在上泌尿道 (腎盂及輸尿管)。膀胱癌的分級(grading)及分期(staging)仍是影響此類病人預後最重要的因素。但是,要能夠精準的篩選需要新輔助性療法之病人,必須找尋更多的預後指標。我們之前的研究證實,病人尿液中可以達到的大豆異黃酮化合物(genistein,daidzein及biochanin-A)濃度,具有不同的抗癌功效。在找尋被大豆異黃酮影響的基因群研究中,EMP2基因是會被大豆異黃酮誘發的其中一個基因。另外,上尿路上皮癌細胞株(如RT-112, KU-19-19, CRL-7930)等可以偵測到染色體19q13的過度表現。而EMP3恰巧落在染色體19q13.3的位置。因此,我們希望研究EMP2 和EMP3在尿路上皮致癌的重要性。在尿路上皮癌模式中,大豆異黃酮可以正相調控EMP2基因的表現。過度表現EMP2會抑制癌細胞株的集落形成及細胞的非貼附性生長,並抑制動物模式中的腫瘤生長。我們也證實,EMP2和整合素V及β3之間有緊密地關係,進一步影響到細胞爬行及貼附能力。以病人檢體的臨床研究發現,EMP2的高度表現會減緩疾病進展,並提高上泌尿道尿路上皮癌病患的存活率。另外,EMP3基因會在ErbB2基因高度表現的尿路上皮癌細胞株(TCC-SUP-N5)中被偵測到。給予trastuzumab藥物進一步確認EMP3會受ErbB2所調控。當EMP3基因在TSGH8301細胞高度表現時,可以經由PI3K/AKT的路徑而有意義的增加細胞生長,並促進癌細胞之爬行能力。但是,EMP3基因高度表現會降低癌細胞與細胞外間質的貼附能力。EMP3也會調控整合素(integrins)的表現,並活化FAK/Src蛋白後,正向調控下游的RhoA/ROCK通路,增加細胞的生物功能。以上尿路上皮癌臨床檢體的研究證實,當ErbB2以及EMP3共同表現時,會促進患者的疾病進展以及轉移進展,並降低患者的存活率。本研究證實,在上尿路上皮癌中EMP2基因扮演抑癌基因的功能,影響整合素之表現,以及細胞的功能。本研究亦釐清,EMP3基因在上尿路上皮癌中扮演致癌基因 (proto-oncogenes)。EMP3與致癌基因ErbB2在上尿路上皮癌有緊密地調控關係。未來可針對EMP2與整合素或EMP3與ErbB2兩者為目標,尋找可能的新治療策略。
英文摘要 Human cancer is the most important cause of death in Taiwan over the past 30 years. Most of the urothelial carcinoma (UC) (90% to 95%) occurs in the urinary bladder, with lower incidence (5% to 10%) in the upper urinary tract (renal pelvis and ureter, UUT-UC). The prognosis of UC patients is related to tumor stage and histological grading; however more indicators are mandatory in the design of neoadjuvant or adjuvant therapy. We showed that genistein, daidzein, and biochanin-A demonstrate differential anticancer effects in the range of human urine excretion. In a molecular profiling experiment to search for genes modulated by isoflavones, epithelial membrane protein 2 (EMP2) is one of the up-regulated candidate genes. In addition, amplification of 19q13 was detected in UC cell lines (RT-112, KU-19-19, CRL-7930), and EMP3 is localized within this chromosomal region. This study was designed to investigate the biological significance of EMP2 and EMP3 in the pathogenesis of UC and their prognostic implication. EMP2 was upregulated by isoflavones at both transcriptional and translational levels. EMP2 overexpression suppressed foci formation, anchorage-independent growth in vitro, and tumorigenicity in SCID mice (all P < 0.05). In addition, a crosstalk between EMP2 and integrins V and β3 was demonstrated in regulation of cell adhesion and migration. Higher EMP2 expression was associated with a better progression-free survival (P = 0.008) and cancer-related death (P < 0.001). In terms of EMP3, we showed a functional crosstalk between ErbB2 and EMP3 in vitro. EMP3 overexpression promoted the proliferation and migration of cancer cells, but suppressed cell adhesion in vitro. EMP3 activated the ErbB2-PI3K-AKT pathway to increase cell growth in vitro. Kaplan-Meier survival estimates of clinical cohort showed that co-expression of ErbB2 and EMP3 is the most important indicator of progression-free (P = 0.018 log-rank test) and metastasis-free survival (P = 0.04; log-rank test) for patients with UUT-UC. EMP2 was identified as a tumor suppressor gene in UC and may be an innovative co-targeting candidate for designing integrin-based cancer therapy. On the contrary, EMP3 is an important prognostic indicator in the selection of patients with UUT-UC for more intensive therapy. EMP3 is an innovative co-targeting candidate for designing ErbB2-based cancer therapy.
論文目次 中文摘要 I
Abstract III
誌謝 V
Contents VII
Table contents X
Figure contents XI
Appendix contents XIII
Abbreviations XIV
Introduction 1
1. Urothelial carcinoma (UC) 1
2. Tumor suppressor genes and Oncogenes in UC 2
3. Genomic aberrations 5
4. EMPs family 6
5. Tetraspain web 9
6. Integrin 10
Materials and Methods 13
1. Cell lines 13
2. Forward subtraction of suppression subtractive hybridization and function
assay 13
3. Constructing EMP2 promoter and luciferase reporter assay 14
4. Stable transfectant of EMP2-GFP, EMP3-GFP 15
5. The shRNA transfection 15
6. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR analysis 16
7. Western blotting 17
8. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay 18
9. Apoptosis analysis 18
10. Cell-cycle distribution analysis 18
11. Immunofluorescent staining and confocal microscopy 19
12. Focus formation assay 19
13. Anchorage-independent cell growth 20
14. Migration assay 20
15. Cell adhesion assay 20
16. Tumorigenicity assay 21
17. Immunocytochemical staining 21
18. Clinicopathological characteristics of study cases 21
19. Immunohistochemical staining 22
20. Statistical analysis 23
Results 24
Part I. Profiling screening by microarray and identification of EMP genes for further investigation
1. Profiling of isoflavone-induced gene expression by SSH 24
2. Modulation of EMPs expression by isoflavones and expression pattern of EMPs in human uroepithelial cells 24
3. Microarray profiling of expression pattern of EMPs in urothelial carcinoma
cells 25
4. Expression pattern of EMPs in human uroepithelial cells 25
Part II. The molecular basis for EMPs in the urothelial carcinogenesis
1. Establishment of EMPs stably overexpressed clones 26
2. Subcellular localization of EMP2 and its significance on foci formation and
anchorage -independent growth 27
3. The effect of EMP2 and EMP3 on cell migration and adhesion 28
4. The tumorigenic effect of EMP2 in vivo 28
Part III. The EMP gene family-related signaling pathway in urothelial carcinogenesis
1. Cross-talk of EMPs with integrins in modulation of biological effects 29
2. Crosstalk of integrins with EMPs and the downstream signaling pathway 30
3. Association of EMP3 expression with ErbB2 in human UC cells in vitro 31
4. The involvement of EMPs in ErbB2-PI3-kinase-Akt pathway 32
Part IV. Prognostic significance of EMPs expression in upper urinary tract urothelial carcinoma (UUT-UC)
1. Prognostic significance of EMP2 in UUT-UC 33
2. Prognostic significance of EMP3 and ErbB2 expression in UUT-UC 33
3. The regulatory mechanism of EMP3 expression in vitro and in vivo 34
Discussion 36
Conclusion 43
References 44
Tables 56
Figures 68
Appendix 94

TABLE CONTENTS
Table 1. Summary of SSH results 57
Table 2. Expression patterns of EMP genes identified by microarray analysis 61
Table 3. Association of EMP2 expression with clinicopathological characteristics 62
Table 4. Prognostic significance of clinicopathological indicators and EMP2 status in
relation to clinical outcome 63
Table 5. Association of EMP3 expression with clinicopathological characteristics of
patients with upper urinary tract urothelial carcinoma (UUT-UC) 64
Table 6. (A) Prognostic indicators for progression-free survival in patients with UUT-UC (B) Prognostic indicators for metastasis-free survival in patients with UUT-UC (C) Prognostic indicators for progression-free survival in patients with ureter cancer (D) Prognostic indicators for progression-free survival in patients with kidney cancer 65
Table 7. Association of expression patterns of ErbB2 and EMP3 with clinicopathologic characteristics of patients with UUT-UC 67

FIGURE CONTENTS
Figure 1. Modulation of EMP2 expression by isoflavones was examined by northern
blotting and luciferase reporter assay 69
Figure 2. Modulation of EMP2 expression by isoflavones and expression of EMPs in
human uroepithelial cells 71
Figure 3. The effect of EMP2 on cell growth 72
Figure 4. The effect of EMP3 on cell growth 74
Figure 5. Subcellular localization of EMP2 75
Figure 6. The effect of EMP2 expression on foci formation and anchorage- independent growth 76
Figure 7. The effect of EMP2 on cell migration and adhesion in vitro 78
Figure 8. The effect of EMP3 on cell migration and adhesion in vitro 79
Figure 9. Tumorigenicity of EMP2 in vivo 80
Figure 10. The interaction of EMPs with integrin members 81
Figure 11. The cross-talk between EMP2 and integrins 82
Figure 12. The cross-talk between EMP2 and integrin in the context of cell
adhesion 83
Figure 13. Identification of EMP3-related signaling pathway 84
Figure 14. Expression of biomarker profile in TCC-SUP and TCC-SUP-N5 cells 85
Figure 15. Association of EMP3 expression with ErbB2 in human urothelial carcinoma
cells in vitro 86
Figure 16. Modulation of ErbB2-PI3K-Akt pathway by EMP3 87
Figure 17. Expression of EMP2 and its prognostic significance in patients with
UUT-UC 88
Figure 18. Prognostic significance of EMP3 RNA expression in patients with UUT-
UC 89
Figure 19. Methylation-specific PCR (MSP) for EMP3 promoter-associated CpG islands
in uroepithelial cell lines 91
Figure 20. The regulation of EMP3 expression in vitro and in vivo 92
Figure 21. Hypothetical model for crosstalk of integrins with EMPs and their downstream signaling pathways 93

APPENDIX CONTENTS
Appendix Table 1. The plasmids and their characteristics utilized in current study 95
Appendix Table 2. List of shRNA sequences and their characteristics utilized in current study 96
Appendix Table 3. The primers utilized in current study 97
Appendix Table 4. The PMP-22/EMP Family Structure domain 99
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