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系統識別號 U0026-2907201612513900
論文名稱(中文) 化療藥物引起的八聚體結合轉錄因子(Oct4)的表達在抗藥性以及膀胱癌復發中所扮演的角色以及調控
論文名稱(英文) Study on the role of chemotherapeutics-induced Octamer-binding transcription factor 4 (Oct4) expression in drug resistance and tumor recurrence in bladder cancer
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 104
學期 2
出版年 105
研究生(中文) 盧佳杏
研究生(英文) Chia-Sing Lu
學號 S58981400
學位類別 博士
語文別 英文
論文頁數 98頁
口試委員 指導教授-吳昭良
召集委員-賴明德
口試委員-陳玉玲
口試委員-洪文俊
口試委員-蔡宗欣
口試委員-蘇五洲
中文關鍵字 八聚體結合轉錄因子  耐藥性  腫瘤復發  膀胱癌  全反式維甲酸 
英文關鍵字 Oct4  drug resistance  tumor recurrence  bladder cancer  all-trans retinoic acid 
學科別分類
中文摘要 在續發性腫瘤復發的常規的化學治療上,後天獲得的抗藥性是主要的挑戰。膀胱癌在所有惡性腫瘤中擁有最高的復發率。儘管原發性腫瘤可以通過手術,化學治療,和放射線治療被移除,腫瘤頻繁地復發並經常發展成侵犯肌肉層的病況。在本研究中,我們研究了抗癌藥物是否會誘導在膀胱癌細胞中八聚體結合轉錄因子Oct4表達,從而獲得耐藥性與腫瘤復發。我們觀察並發現在122個為非肌層浸潤型高期別的膀胱移形性上皮細胞惡性腫瘤的臨床檢體中,Oct4 的表達與腫瘤的復發率有關聯性。細胞實驗發現,化學治療藥物處理會增加膀胱癌細胞中Oct4的表達。值得注意的是,cisplatin治療會增加CD44抗原-陽性膀胱癌細胞中Oct4的表達,CD44為類癌症幹細胞亞群之細胞標誌。在細胞中當增強Oct4的表現時會減少膀胱癌細胞的藥物敏感性,而抑制Oct4的表現則會增強膀胱癌細胞的藥物敏感性。而且腫瘤細胞過量表達Oct4,無論是細胞實驗或是動物實驗皆對 cisplatin的反應不佳。關於臨床相關意義,實驗結果發現藉由全反式維甲酸抑制Oct4,可協同地增加膀胱癌細胞對cisplatin的敏感性。此外, cisplatin與全反式維甲酸的合併治療比起單獨給予cisplatin更能的抑制腫瘤生長。我們進一步經由啟動子活性分析與染色質免疫沉澱證明,Oct4可以藉由結合到多重抗藥性基因MDR1啟動子上的Oct4反應區段而活化基因表現。這些結果指出Oct4參與化療藥物排出。最後,在膀胱癌病人的腫瘤細胞中,無論是與低表現Oct4 或是MDR1的組別相比,高表現Oct4或是MDR1的組別,則患者皆具有較短的無復發時間區間。因此我們推測Oct4參與腫瘤增加耐藥性的過程,並且抑制Oct4可能成為避開耐藥性的一種治療策略。
英文摘要 Acquisition of drug resistance to conventional chemotherapy is a challenge in treating recurrent cancer. Bladder cancer has the highest recurrence rate of any malignancy. Although primary tumors can be eliminated by surgery, chemotherapy, and radiotherapy, the tumors recur frequently and progress to muscle-invasive disease. Here we investigated whether anticancer drugs induced Oct4 expression and ultimately results in tumor recurrence in bladder cancer. We identified a positive correlation of the expression levels of Oct4 with the rate of tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma. Chemotherapy induced Oct4 expression in bladder cancer cells. Notably, treatment with cisplatin increased CD44-positive bladder cancer cells expressing Oct4, representing cancer stem-like cell subpopulation. Overexpression of Oct4 reduced, whereas knockdown of Oct4 enhanced, drug sensitivity in bladder cancer cells. Furthermore, there was a poor response to cisplatin treatment in vivo when tumor cells overexpressed Oct4. In terms of clinical relevance, inhibition of Oct4 by all-trans retinoic acid synergistically increased sensitivity to cisplatin in bladder cancer cells. Furthermore, the combination of cisplatin and all-trans retinoic acid was superior to cisplatin alone in suppressing tumor growth. At last, Luciferase reporter and chromatin immunoprecipitation (ChIP) assays demonstrated that Oct4 could transactivate the MDR1 promoter by binding to the Oct4 response element. These results indicated Oct4 involved in chemodrugs efflux. Patients with Oct4 and/or MDR1 high-expressing tumors were associated with shorter recurrence-free intervals compared with patients with Oct4 and/or MDR1 low-expressing tumors. Therefore, our findings provide evidence that Oct4 can mediate acquired drug resistance to anticancer drugs, and implicate that targeting Oct4 may be a therapeutic strategy to circumvent drug resistance.
論文目次 Chinese abstrate I
Abstract II
Acknowledgements IV
Contents V
List of figures and tables X
Abbreviations XIII
Introduction 1
1. Platinum-based agents for cancer chemotherapy 1
1.1. Cancer chemotherapy 1
1.2. Platinum-based drugs 1
1.3. Mechanisms of tumor resistance to Platinum-based drugs before and after platinum reaching target DNA 2
1.4. Signal pathway induced by cisplatin results in acquired drug resistance 3
2. Cancer stem cells display similar characteristics to embryonic stem cells 4
2.1. Embryonic stem cells 4
2.2. Cancer stem cells 4
2.3. Stemness signaling pathways of CSCs contribute to drug resistance and poor prognosis of patients 5
3. Oct4 plays an important role both in maintaining ESCs and CSCs 6
3.1. Oct4 structure 6
3.2. Oct4 plays an important role in maintaining ES cells 7
3.3. Oct4 expression is found in cancer tissues and cancer cell lines 7
3.4. Regulation of Oct4 in tumor cells 8
4. Bladder cancer 9
4.1. Bladder cancer treatment 9
4.2. Oct4 is highly expression in bladder cancer predict poor prognosis 10
5. Cross-drug resistance 11
5.1. ATP-binding cassette (ABC) transporters 11
5.2. Multiple-drug resistance protein 1 (MDR1) is overexpressed in bladder cancer 12
Rationale and hypothesis 13
Specific aims 14
Materials and methods 15
1. Materials 15
1.1. Clinical specimens 15
1.2. Cells 15
1.3. Animal 15
1.4. Plasmids 16
1.5. Short hairpin RNA (shRNA) 16
1.6. Oligonucleotides 16
1.7. Antibodies 17
1.8. Reagents and kits 18
1.9. Equipment and software 18
2. Methods 19
2.1. Cell culture 19
2.2. Mice 19
2.3. Plasmids construction 19
2.4. Quantitative real-time RT-PCR analysis 22
2.5. Luciferase reporter assay 22
2.6. ChIP assay 23
2.7. Immunohistochemistry 23
2.8. Immunoblotting 24
2.9. Immunofluorescence 24
2.10. Rhodamine 123 efflux assay 25
2.11. Drug sensitivity assay 26
2.12. Drug interaction analysis 26
2.13. Animal experiments 26
2.14. Statistical analysis 27
Results 28
Part I: Chemotherapeutics-induced Oct4 expression contribute to drug resistance and tumor recurrence in bladder cancer 28
1.1. Expression levels of Oct4 are increased in bladder cancer and positively correlated with tumor recurrence 28
1.2. Expression levels of Oct4 are increased in recurrent bladder cancer 28
1.3. Expression of Oct4 is increased in bladder cancer cells following chemotherapeutic treatment 29
1.4. CD44-positive cells expressing Oct4 are increased in bladder cancer cells following cisplatin treatment 30
1.5. CD44-positive cells expressing Oct4 are increased in bladder tumor xenografts following cisplatin treatment 31
1.6. Overexpression of Oct4 in bladder cancer confers resistance to cisplatin in vitro and in vivo 31
1.7. Knockdown of Oct4 expression enhances sensitivity of bladder cancer cells to various chemotherapeutic agents 33
1.8. ATRA synergistically enhances cisplatin-induced cytotoxicity in bladder cancer cells 33
1.9. Combination treatment of cisplatin with ATRA inhibits the growth of bladder tumor 34
Part II: Oct4 transactivates MDR1 gene expression 36
2.1. Knockdown of Oct4 reduces MDR1 mRNA expression and increases Rhodamine 123 accumulation in bladder cancer cells 36
2.2. Oct4 transactivates the MDR1 promoter 36
2.3. Expression of both Oct4 and MDR1 was down-regulated in the TCCSUP cells following ATRA treatment 38
2.4. Expression levels of MDR1 are increased in bladder cancer and positively correlated with tumor recurrence 38
2.5. Expression levels of Oct4 and MDR1 are increased in recurrent bladder cancer and positively correlated with tumor recurrence 39
Discussion 40
1. Oct4 is overexpressed in patients with recurrent bladder tumor and is essential in drug resistance 40
2. Increased Oct4 in cisplatin treatment of bladder cancer cells may through HIF-2α and NF-κB 40
3. Bladder cancer cells undergo CSC-like changes after exposure to cisplatin 41
4. Oct4 either directly or indirectly contributes to the cross-resistance of bladder cancer cells to the chemotherapeutic drugs 43
5. Oct4 transactivate MDR1 may contributes to the cross-resistance of bladder cancer cells to the chemotherapeutic drugs 44
6. The role of Oct4 in the resistance of bladder cancer cells to different anticancer drug needs to be further investigated 45
7. Inhibition of Oct4 may be a potentially effective therapeutic strategy against cancer a for chemotherapy and/or radiotherapy 46
8. ATRA provides multiple advantages for cancer therapy 47
Conclusion 49
References 50
Figures 59
Table 95
Appendix 96


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