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研究生:游珮寧
研究生(外文):Pei-Ning Yu
論文名稱:探討微小核醣核酸-29(miR-29)在卵巢癌中對cisplatin抗藥性的影響
論文名稱(外文):Study on the effect of miR-29 on cisplatin resistance of ovarian cancer
指導教授:林雅雯林雅雯引用關係
指導教授(外文):Ya-Wen Lin
口試委員:林雅雯司徒惠康賴鴻政楊慕華陳永恩
口試委員(外文):Ya-Wen LinHuey-Kang SytwuHung-Cheng LaiMuh-Hwa YangMichael W. Y. Chan
口試日期:2013-09-05
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:102
語文別:英文
論文頁數:84
中文關鍵詞:微小核醣核酸-29卵巢癌cisplatin抗藥性
外文關鍵詞:miR-29ovarian cancerisplatin resistance
相關次數:
  • 被引用被引用:0
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卵巢癌是世界上常見且致死率極高的婦科腫瘤之ㄧ,而化療抗藥性則是臨
床治療卵巢癌很重要的問題。在過去的研究中,我們建立並運用一個特殊的細胞
模式證明,由卵巢癌細胞株分離出的ㄧ小群細胞比原始細胞株具有更強大的
cisplatin 抗藥性(cisplatin resistance)。然而,此細胞之cisplatin 抗藥性的機制並不
清楚。微小核醣核酸(MicroRNAs )是一小片段且不會轉譯成蛋白質的核醣核酸,
目前已證實微小核醣核酸與癌症細胞的生物行為有高度相關。在本論文,我們探
討微小核醣核酸是否會影響卵巢癌的cisplatin 抗藥性。利用微小核醣核酸微陣列
(miRNA array)及即時定量聚合酵素連鎖反應(quantitative RT-PCR data)的實驗結
果發現,具有cisplatin 抗藥性的卵巢癌細胞其微小核醣核酸-29(miR-29)的表現
量較低。在CP70、 HeyC2、SKOV3、和 A2780 等卵巢癌中改變微小核醣核酸
-29 的表現可影響細胞對cisplatin 的敏感性。減少細胞中的微小核醣核酸-29 會
透過增加collagen type I alpha 1 (COL1A1)、活化ERK1/2 及抑制GSK3活性以減
少cisplatin 引起的細胞死亡。此外,在給予cisplatin 時,減少微小核醣核酸-29
也會減少caspase-9 和caspase-3 的活化。活體實驗部分,我們則是發現大量表現
微小核醣核酸-29 或是給予cisplatin 時同時增加微小核醣核酸-29 均會有效的抑
制卵巢癌細胞(CP70 細胞株)在小鼠體內的生長。此外,我們也發現微小核醣核
酸-29a 表現量較高的卵巢癌病人,其存活率較微小核醣核酸-29a 表現量低的病
人高。綜合我們的實驗結果我們證明抑制微小核醣核酸-29 會增加卵巢癌細胞的
cisplatin 抗藥性,增加微小核醣核酸-29 則可為投與cisplatin 時的致敏劑,因此可
能具有治療卵巢癌的潛在價值。
Epithelial ovarian cancer (EOC) is a common gynecologic malignancy and is
one of the 10 most common causes of death by cancer in women. Drug resistance is
an obstacle to the treatment of ovarian cancer. Using a unique cell model, we have
proven previously that a subpopulation of ovarian cancer cells is more resistant to
cisplatin than are the original cells. However, the underlining mechanisms of
cisplatine resistance in the subpopulation are still unknown. MicroRNAs (miRNAs),
small noncoding RNAs, are involved in many biological events in cancer cells. In this
study, we explored whether miRNAs are involved in cisplatin resistance of ovarian
cancer cells. Our miRNA array and quantitative RT-PCR data showed that
cisplatin-resistant cells expressed a lower level of miR-29a/b/c. Manipulation of
miR-29 expression modulated cisplatin sensitivity of CP70, HeyC2, SKOV3, and
A2780 ovarian cancer cells. Knockdown of miR-29a/b/c increased the ability of cells
to escape cisplatin-induced cell death partly through upregulation of collagen type I
alpha 1 (COL1A1) and increased the activation of ERK1/2 and inactivation of GSK3.
When combined with cisplatin treatment, knockdown of miR-29 decreased the
amount of the active form of caspase-9 and caspase-3. Ectopic expression of miR-29
alone or in combination with cisplatin treatment efficaciously reduced the
tumorigenicity of CP70 cells in vivo. In further investigation, we also found that the ovarian cancer patients with high expression of miR-29a had better overall survival
rate. Our data show that downregulation of miR-29 increases cisplatin resistance in
ovarian cancer cells. Taken together, these data suggest that overexpression of miR-29
is a potential sensitizer to cisplatin treatment that may have therapeutic implications.

Table of contents
ABSTRACT (Chinese)………………………………………………………………I
ABSTRACT (English)……………………………………………………………….II
INTRODUCTION……………………………………………………………………1
Epithelial ovarian cancer (EOC)……………………………………………………… 1
Drug resistance in epithelial ovarian cancer……………………………………… 1
MicroRNAs (miRNAs)……………………………………………………………….. 5
MicroRNAs and ovarian cancer…………………………………………………...7
The association of microRNAs with drug resistance in ovarian cancer ………….7
miR-29 family……………………...........................................................................9
The role of miR-29 family in cancer..........................................................11
SPECIFIC AIMS………………………………………………………………… ..15
Materials and Methods…………………………………………………………… ..15
Patients and clinical samples………………………………………………….….15
Cell lines…………………………………………………...……………………..15
RNA isolation, reverse transcription (RT), and quantitative polymerase chain
reaction (PCR)……………………………………......................……………......18
Cisplatin sensitivity (cell death), cell viability, and cell cycle assay…………….19
Cell viability assay (MTS assay)…………………………………………………20
Transfection………………..…………………………………………………......20
microRNA inhibitor, siRNA and plasmid………………......................................21
Luciferase reporter gene assay..………………………………………………….22
Western blot analysis...........................................................................22
Type I collagen coating…………………………………………………………. .23
Flow cytometric analysis (evaluation of stemness markers)…………………......23
Paclitaxel and epirubicin treatment ……….…………………………………......24
Analysis of tumorigenicity in vivo……...……………………………………......24
Cell transformation assay (Foci formation assay)……………………………......25
The sequence of oligonucleotide..……………………………………………......25
Statistical analysis………………………………………………………………..25
RESULTS……………………………………………………………………………26
Expression of miR-29a/b/c differs between cisplatin-resistant ovarian cancer cell
lines………………………………………………………………………………28
Downregulation of miR-29 promotes resistance to cisplatin-induced cell death
in ovarian cancer cells……………………………………………………………29
Collagen type I alpha 1 (COL1A1) is a target of miR-29………………………...30
Activation of ERK1/2, GSK3, caspase-9, and caspase-3 is involved in the effects
of miR-29 on cisplatin resistance…………………………………………………33
Overexpression of miR-29 in CP70 cells increases cisplatin sensitivity and
suppresses tumor formation in NOD/SCID mice………………………………...34
The clinical value of the miR-29 family in ovarian cancer patients……………...36
DISCUSSION……………………………………………………………………….38
Discussion on materials and methods………….………………………………...38
Discussion on results…………………………...………………………………...41
REFERENCES…………………………………………………………………….. .47
Tables
Table 1. The clinicopathological characteristics of ovarian cancer patients...57
Table 2. Microarray analysis of the miRNA expression between CP70sps and CP70 ovarian cancer cells………58
Table 3. Correlations of the expression of miR-29a/b/c with clinicopathological
characteristics in ovarian cancer patients............................................59
Figures
Figure 1. Expression of microRNAs in differential cisplatin-resistant ovarian cancer cells………………………60
Figure 2. The IC50 cisplatin dosage was determined…………………………..61
Figure 3. Modulation of miR-29 affects cisplatin sensitivity in CP70 cells......62
Figure 4. The effects of miR-29 on the viability and cell cycle progression of CP70 cells………………………63
Figure 5. Modulation of miR-29a/b/c affects cisplatin sensitivity in A2780 cells…………………………64
Figure 6. The cisplatin sensitivity and miR-29a/b/c expression of ovarian cancer cell lines………………65
Figure 7. Modulation of miR-29 affects cisplatin resistance in HeyC2 and SKOV3 cells…………66
Figure 8. The effects of miR-29 on the viability and cell cycle progression of CP70 cells……..…………67
Figure 9. Evaluation the drug sensitivity in ovarian cancer cells with modulated miR-29a/b/c expression....68
Figure 10. COL1A1 is a target of miR-29………………69
Figure 11. Knockdown of COL1A1 sensitizes CP70 and A2780 cells to cisplatin treatment…………………………………70
Figure 12. Type I collagen reduces cisplatin-induced cell death in A2780 cells……………………………………………………71
Figure 13. Modulation of COL1A1 alters the effects of miR-29 on cisplatin sensitivity………………………………72
Figure 14. The phosphorylation of AKT, ERK1/2 (Thr202/Tyr204), and GSK3(Ser9) in miR-29a/b/c knockdown
cells………73
Figure 15. The phosphorylation of ERK1/2 (Thr202/Tyr204) and GSK3(Ser9)in CP70 and A2780 cells
cultured in type I collagen-coated dishes……………………74
Figure 16. The active form of caspase-9 and caspase-3 in miR-29a/b/c knockdown cells.……………………………75
Figure 17. Overexpression of miR-29 in implanted CP70 cells in NOD/SCID mice………………76
Figure 18. Overexpression of miR-29 in CP70 cells increases cisplatin sensitivity and suppresses tumor
formation in NOD/SCID mice………77
Figure 19. miR-29 regulates stemness-associated markers in implanted tumors.....78
Figure 20. miR-29 regulates stemness-associated markers in an ovarian cancer cell line………………………………79
Figure 21. Overexpression of miR-29 in CP70 cells reduced transformation ability…………80
Figure 22. The correlation between miR-29 expression and the overall survivalof ovarian cancer patients......81
Figure 23. The correlation between miR-29 expression and COL1A1 expression in ovarian cancer patients…………………82

Supplemental Figure
Supplemental Figure 1. Map of pCDNA6.2 GW/EmGFP-miR neg and pCDNA6.2 GW/EmGFP-miR 29…………………....83
Supplemental Figure 2. Map of pGL3.1 control, pGL3.1 control-COL1A1 3’UTR wt and pGL3.1 control-COL1A1 3’UTR mutant…………………………84


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