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系統識別號 U0026-2908201110424300
論文名稱(中文) 化學治療藥物導致微衛星不穩定及抑制其現象的化合物之發現
論文名稱(英文) Chemotherapeutic agents cause microsatellite instability and which is preventable
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 99
學期 2
出版年 100
研究生(中文) 紀智瑛
研究生(英文) Jhih-Ying Chi
學號 t16984081
學位類別 碩士
語文別 英文
論文頁數 77頁
口試委員 指導教授-張玲
口試委員-蔣輯武
口試委員-李政昌
中文關鍵字 大腸癌  微衛星不穩定  DNA錯誤配對修復機制  化學治療藥物 
英文關鍵字 Colorectal cancer  Microsatellite instability  DNA mismatch repair  chemotherapeutic agent 
學科別分類
中文摘要 DNA錯誤配對修復機制(Mismatch repair, MMR)能夠校正微衛星的重複序列在DNA複製的過程時產生的錯誤配對,即微衛星不穩定(Microsatellite instability, MSI)。DNA錯誤配對修復機制因子會因為hMLH1、hMSH2或hMSH6基因突變或過度甲基化在hMLH1啟動子上而失去活性,並造成為MSI,而這些現象常發生在大腸癌上。MMR基因的缺失,容易造成微衛星的不穩定並且增加大腸癌的發生率及對藥物產生抗藥性。近年來有文獻顯示有些MMR基因缺失的病人在化療治療後會產生繼發性的癌症。為了了解化學治療藥物在微衛星不穩定的造成,我們已經建立帶有雙螢光的微衛星不穩定報導基因,利用(CA)13的微衛星序列以及(N)ctl隨機序列作為大腸癌細胞的報導基因。流式細胞儀的結果顯示,MMR缺失的HCT116大腸癌細胞 (HCT116-(CA)13)在四種化療藥物(Lomustine, Methotrexate, Etoposide與Vinblastine)處理三天後,皆隨著濃度的增加使得(CA) 13重複序列框移突變增加。且相較於MMR缺失的HCT116大腸癌細胞 (HCT116-(N)ctl)以及帶有正常MMR的HCT116+ch3大腸癌細胞(HCT116+ch3-(CA)13),HCT116-(CA)13可表現較高的框移突變。由聚合酶連鎖反應發現,美國國家癌症機構所建立的5個微衛星標誌及11個位在基因編碼區的微衛星,發現Methotrexate、Etoposide與Vinblastine藥物會改變HCT116-(CA)13細胞的核酸重複序列,像是hMSH6、HDAC2、caspase 5、TGFβRII、exportin 1、MBD4和IGF2R基因,而在HCT116+ch3-(CA)13細胞上是沒有改變的。其中我們發現化學治療藥物會降低DNA錯誤配對修復的蛋白質或是DNA損害時會進行修補的蛋白質表現,像是ATR、 hMSH2、hMSH6、CHK1及hMLH1。
我們發現化合物x和y能在不影響細胞存活率的情況下,抑制化學治療藥物所誘導的微衛星不穩定。這些發現顯示這四個化學治療藥物是微衛星不穩定的誘導者,這可以解釋為什麼在化學治療藥物治療過後的癌細胞可以偵測到微衛星不穩定的發生率增加。其目的是找出會誘導或抑制微衛星不穩定的藥物,有助於在給病人的用藥上能對症下藥和個人化醫療。
英文摘要 DNA mismatch repair (MMR) system corrects replication errors, which often occur in microsatellites. MMR is frequently inactivated in colorectal cancer by mutations in MMR genes such as hMLH1, hMSH2 and hMSH6 or by epigenetic silencing of the hMLH1 promoter. Manifested as microsatellite instability (MSI), MMR deficiency contributes to colorectal cancer pathogenesis and drug resistance. Growing evidence indicates that MMR deficiency is also widespread among secondary cancers in patients after receiving chemotherapy. To understand the role of anti-cancer drugs in MSI development, I utilized a newly developed dual-fluorescence reporter system harboring an exogenous (CA)13 microsatellite and (N)ctl random sequence in human colorectal cancer cells to identify MSI-modulating agents. Flow cytometric results show that lomustine, methotrexate, etoposide and vinblastine increased the frameshift mutation frequency of the (CA)13 microsatellite in a dose-dependent manner. Compared to MMR-deficient HCT116-(N)ctl cells and MMR-proficient HCT116+ch3-(CA)13 cells, test anticancer drugs displayed a higher frameshift-inducing ability in MMR-deficient HCT116-(CA)13 cells. Methotrexate, etoposide and vinblastine altered one out of five NCI-recommended microsatellite loci in MMR-deficient but not MMR-proficient cells. All test drugs induced frameshift mutations in the coding microsatellite of hMSH6, HDAC2, caspase 5, TGFβRII, exportin 1, MBD4 and/or IGF2R genes in subpopulation of HCT116-(CA)13 cells. The test drugs also decreased the protein levels of ATR, hMSH2, hMSH6 and CHK1 and/or hMLH1, which are key components of the MMR system and DNA damage response. Furthermore, I found that Compounds x and y were able to suppress drug-induced frameshift mutations without affecting drug-induced cytotoxicity. My findings of four test chemotherapeutic agents as MSI inducers, may in part explain clinical observation of high MSI frequency in chemotherapy-related secondary cancers. Identification of MSI-inducing anticancer drugs and MSI-suppressing compounds will allow strategic management of MSI development in cancer patients who are receiving chemotherapy.
論文目次 ABSTRACT III
1. INTRODUCTION 1
1.1 Microsatellites 1
1.2 Microsatellite instability (MSI) 2
1.3 DNA mismatch repair system (MMR) 4
1.4 Chemotherapy-related secondary cancer displays MMR deficiency 7
1.5 Colorectal cancer (CRC) 8
1.6 MSI and drug resistance 10
1.7 Hypothesis 11
1.8 Specific Aims 11
2. MATERIALS AND METHODS 13
2.1 Cell lines, plasmids and transfection 13
2.2 Stable clone generation 13
2.3 Microsatellite sequencing 14
2.4 MTT assay 15
2.5 Treatment of chemotherapeutic agents 16
2.6 Flow Cytometry 16
2.7 PCR-based microsatellite instability assay 17
2.8 Western blot analysis 18
2.9 DCFH oxidation assay by flow cytometry 19
3. RESULTS 21
3.1 Generation of stable Transfectants harboring dual fluorescence reporters with frameshift mutations 21
3.2 The cytotoxicity of chemotherapeutic agents in MMR-deficient and MMR-proficient cells 22
3.3 Lomustine (CCNU) increases frameshift mutations in HCT116 and HCT116+ch3 derivatives 22
3.4 Methotrexate (MTX) increases frameshift mutations in HCT116 and HCT116+ch3 derivatives 23
3.5 Etoposide (ETO) increases frameshift mutations in HCT116 and HCT116+ch3 derivatives 24
3.6 Vinblastine (VBL) increases frameshift mutations in HCT116 and HCT116+ch3 derivatives 25
3.7 CCNU and MTX restore RFP fluorescence by deleting one (CA) unit in the (CA)13 microsatellite 25
3.8 MTX induces microsatellite instability in MMR-deficient and not MMR-proficient cells 26
3.9 Chemotherapeutic agents induces frameshift mutations in MMR-deficient and not MMR-proficient cells 27
3.10 Chemotherapeutic agents decrease the steady-state level of MMR proteins in human colorectal cancer cells 28
3.11 Compounds x and y suppress frameshift mutations induced by chemotherapeutic agents without affecting their cytotoxicity in HCT116-(CA)13 cells 28
3.12 Compound x reduces MTX-induced MSI HCT116-(CA) 13 cells 29
3.13 ROS generated by chemotherapeutic agents is insufficient to induce MSI and frameshift mutations in HCT116-(CA)13 cells 30
4. DISCUSSION 32
5. REFERENCES 38
6. TABLES 45
Table 1. Chemosensitivity of MMR-deficient colorectal cancer cells 45
Table 2. Human colorectal cancer cell lines in this study 45
Table 3. Chemotherapeutic agents’ concentrations. used in this study 45
Table 4. Microsatellite motifs of NCI-recommended markers and MMR target genes in the microsatellite instability 46
Table 5. Antibodies used in this study 47
Table 6. Estimation of the in-frame mutation detection limits 47
7. FIGURES 48
Figure 1. Generation of HCT116+ch3-derived stable cell lines harboring the dual-fluorescence reporter containing the (CA)13 microsatellite. 48
Figure 2. Generation of SW480-derived stable cell lines harboring the dual-fluorescence reporter containing the (CG)13 microsatellite. 49
Figure 3. Effects of chemotherapeutic agents on the viability of human colorectal cancer cells. 50
Figure 4. Effects of lomustine (CCNU) on the viability and the frameshift mutation frequency of HCT116 and HCT116+ch3 derivatives. 52
Figure 5. Effects of methotrexate (MTX) on the viability and the frameshift mutation frequency of HCT116 and HCT116+ch3 derivatives. 54
Figure 6. Effects of etoposide (ETO) on the viability and the frameshift mutation frequency of HCT116 and HCT116+ch3 derivatives. 56
Figure 7. Effects of vinblastine (VBL) on the viability and the frameshift mutation frequency of HCT116 and HCT116+ch3 derivatives. 58
Figure 8. CCNU and MTX deletes one unit of the (CA)13 microsatellite in the genomic DNA of HCT116-(CA)13 cells. 59
Figure 9. Methotrexate but not other test chemotherapeutic agents induce microsatellite instability in MMR-deficient HCT116-(CA)13 cells. 61
Figure 10. Chemotherapeutic agents induce frameshift mutations in coding microsatellites in HCT116-(CA)13 cells. 64
Figure 11. Effects of chemotherapeutic agents on the steady-state protein levels of MMR and DNA damage components in human colorectal cancer cells. 66
Figure 12. Effects of Compounds x and y on the cytotoxicity of chemotherapeutic agents in HCT116-(CA)13 cells. 67
Figure 13. Compounds x and y decrease the frameshift mutation frequency induced by CCNU, MTX, ETO and VBL in HCT116-(CA)13 cells. 68
Figure 14. Compound x prevents MTX from increasing microsatellite instability and frameshift mutations in HCT116-(CA)13 cells. 70
Figure 15. The effect of Compound x on the ROS level induced by anti-cancer drugs in HCT116 cells. 71
8. ABBREVIATION LIST 73
9. APPENDICES 75
Appendix 1:The role of DNA mismatch repair in microsatellite stability 75
Appendix 2:A schematic function of DNA mismatch repair 76
Appendix 3:Representative target genes in tumors with high-frequency MSI (MSI-H) 77
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