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研究生(外文):Chao-Ching Chang
論文名稱(外文):The significance of Oct-3/4 expression in bladder cancer and its potential as a therapeutic target
指導教授(外文):Chao-Liang Wu
外文關鍵詞:metastasisOct-3/4bladder canceroncolytic adenovirustumor progression
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腫瘤細胞和胚胎幹細胞在生長上展現相似的能力,包括可以持續生長、還未分化狀態、以及具有侵入性的能力。由此,有其必要研究胚胎發育與腫瘤發生相關基因的表現。當不正常的表現某些胚胎時期的同源異形基因 ( Homeobox genes ) 可能會造成腫瘤的生成以及改變腫瘤的特性。Oct-3/4基因屬於同源異形基因的一員又稱作POU5F1,是胚胎幹細胞自我更新能力上關鍵的調控者。Oct-3/4只特定的表現在胚胎幹細胞以及某些腫瘤細胞上。此研究中,我們利用半定量RT-PCR以及西方點墨方法研究Oct-3/4在57個膀胱癌腫瘤檢體以及幾株膀胱癌細胞珠中的表現情形。我們發現︰幹細胞表達的標記基因Oct-3/4過量表達於人類膀胱癌組織以及膀胱癌細胞株上。然而,為何會表達Oct-3/4基因以及表達的細胞來源為何仍須進一步研究。在此研究中,我們發現Oct-3/4表現量與膀胱癌在臨床預後診斷有關,相較於中量或低量表現的膀胱癌組織,在表達較多Oct-3/4的膀胱癌組織中,發現病人有更進一步疾病的惡化、增加腫瘤的轉移以及預後存活率降低等。我們研究膀胱癌細胞株過量表達Oct-3/4,結果發現促進細胞的移動、侵入性、以及增加體內腫瘤轉移的能力並且發現Oct-3/4過量表現調控增加纖維母細胞生長因子 (FGF)-4以及間質金屬結合蛋白脢 (MMP)-2、MMP-9、MMP-13的表現。Oct-3/4特異性表現在膀胱癌腫瘤細胞或許可以當做腫瘤基因治療的標的基因。因此,更進一步,我們利用Oct-3/4 啟動子驅動E1B-55 kD-缺失的腺病毒 (Ad5WS4) 發現可以有效治療膀胱癌小鼠動物模式。總結,在此研究中,我們發現Oct-3/4或許可以當作膀胱癌預後徵兆的指標及治療膀胱癌的重要標的基因。
Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. It is important to study genes associated with embryogenesis and tumorigenesis. Deregulated expression of certain embryonic homeobox genes is potentially correlated with tumorigenesis and can affect some aspects of tumor behavior. Homeobox gene, Oct-3/4 (also named as POU5F1) is a key regulator of selfrenewal in embryonic stem cells and specifically expressed in embryonic stem cells and certain tumor cells. We used semiquantitative RT-PCR and Western blotting to examine the expression of Oct-3/4 in 57 bladder tumor tissues and several bladder tumor cell lines. Here we demonstrate that expression of stem cell marker Oct-3/4 in human bladder transitional cell carcinoma samples and cell lines. However, the origin of Oct-3/4-expressing tumor cells needs to be identified. More importantly, we show in clinical samples bladder tumors with intense Oct-3/4 expression are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. We used bladder cancer cell lines to confirm that Oct-3/4 overexpression promotes migration, invasion, and metastasis, as well as upregulates fibroblast growth factor (FGF)-4 and matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13 productions. Oct-3/4 highly expressed in bladder cancer cells may be a potential target for cancer therapy. Therefore, we also illustrate the antitumor efficacy of E1B-55 kD-deleted adenovirus driven by Oct-3/4 promoter (Ad5WS4) in syngeneic tumor models. Our results implicate that Oct-3/4 may serve as a novel tumor biological and prognostic marker as well as a potential therapeutic target for bladder cancer.
Chinese abstract ……………I
Abstract ……………II
Contents Table ……………IV
Index of Figures ……………VII
Index of Tables ……………X
Index of Supplementary Figures ……………XI
Abbreviations ……………XII
Introduction ……………1
1. Tumorigenesis and homeobox gene ……………1
2. Oct-3/4 ……………1
2.1. Oct-3/4 background ……………1
2.2. Oct-3/4 and cancer ……………2
2.3. Oct-3/4 and target genes ……………3
2.4. Oct-3/4 and its regulations ……………4
3. Cancer gene therapy ……………4
4. Adenovirus ……………5
5. Conditionally replicative adenoviruses (CRAds) ……………6
5.1. Genetic complementation-type CRAds ……………6
5.2. Transcomplementation-type CRAds ……………7
6. Bladder cancer ……………8
Specific Aim ……………10
Materials and Methods ……………11
Results ……………27
1. Oct-3/4 may be a novel tumor biological and prognostic marker of superficial bladder TCC ……………27
2. Oct-3/4 overexpression enhances whereas knockdown of Oct-3/4 expression reduces migration and invasion of bladder cancer cells ……………29
2.1. Generation of bladder cell lines stably overexpressing Oct-3/4 ……………29
2.2. Transcriptional effects of Oct-3/4 overexpression in human bladder cancer cells ……………30
2.3. Oct-3/4 enhances migration and invasion ……………30
3. Oct-3/4 overexpression promotes metastasis in animal tumor models ……………32
4. Oct-3/4 upregulates FGF-4 and MMP expressions in bladder cancer cells ……………32
5. Therapeutic efficacy of E1B-55 kD-deleted adenovirus regulated by Oct-3/4 promoter for bladder cancer ………………34
5.1. Oct-3/4 promoter is specifically active in bladder cancer cells, not in normal cells ……………34
5.2. Comparison of Ad5WS4 and Ad5WS1 ……………35
5.3. Ad5WS4 exerts cytolytic effect in vitro against bladder cancer cells ……………35
6. Oct-3/4 overexpression did not affect CAR expression and efficiency of adenovirus-mediated gene transfer ……………36
7. Antitumor effects of Ad5WS4 on murine bladder tumor model ……………36
Discussion ……………38
Conclusion ……………44
References ……………45
Appendix of Figures ……………55
Appendix of Tables ……………80
Appendix of Supplementary Figures ……………83
Curriculum Vitae ……………89
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