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研究生：	董家豪 Dong, Jia-Hao
論文名稱：	微小核醣核酸microRNA-509-3p在卵巢癌復發所扮演的角色 The role of microRNA-509-3p in recurrence of ovarian cancer
指導教授：	洪澤民 Hong, Tse-Ming
共同指導教授:	陳玉玲 Chen, Yu-Ling
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	63
中文關鍵詞：	卵巢癌、miR-509-3p 、鉑類藥物抗藥性、PGM1
外文關鍵詞：	ovarian cancer, platinum resistance, miR-509-3p, PGM1
相關次數：	點閱：72 下載：5
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卵巢癌的病人在接受治療後的高復發率，使其成為婦女癌症中死亡率最高的癌症，大部分的病人在接受以鉑類藥物(platinum)為主的化療過後產生抗藥性而癌症復發，我們目標是找到一個microRNA參與在卵巢癌的復發的過程。和原位卵巢腫瘤比較，miR-509-3p的表現量在復發腫瘤呈現下降趨勢，而從卵巢癌細胞株A2780中篩出對鉑類藥物具抗藥性之細胞株A2780CP70中，miR-509-3p同樣呈現下降趨勢且幾乎不表現。在鉑類抗藥性株A2780CP70中過度表現miR-509-3p造成其對鉑類藥物更敏感；在A2780中抑制miR-509-3p的表現使其對鉑類藥物抗藥性提高。在卵巢癌細胞株SKOV-3中過度表現miR-509-3p同樣造成其對鉑類藥物敏感，而對紫杉醇無顯著差異。藉由微陣列分析方式找到一個可能受到miR-509-3p調控的基因, phosphoglucomutase-1 (PGM1), 可能導致細胞對鉑類藥物抗藥性提高，但目前尚無直接證據連結PGM1與鉑類藥物抗藥性的相關性，我們發現在A2780CP70中過度表現miR-509-3p會抑制PGM1表現量，在A2780抑制miR-509-3p導致PGM1表現上升。miR-509-3p能夠藉由PGM1 3’UTR調控報告基因(luciferase)的表現。最後，RNAi抑制A2780CP70中PGM1表現量增加其對鉑類藥物的敏感度。總和以上，臨床檢體分析miR-509-3p在復發卵巢腫瘤中表現量下降，而miR-509-3p能藉由抑制PGM1表現而增強卵巢癌細胞對鉑類藥物的敏感度，間接暗示miR-509-3p在卵巢癌復發中所扮演的角色，也許調控miR-509-3p合併鉑類化療對未來卵巢癌治療上具有應用性。

Ovarian cancer has the highest mortality among gynecologic malignancies because of the high recurrence rates. The large majority of patients treate with platinum-based chemotherapy developed acquired platinum resistance and, subsequently, cancer recurrence. Resistance of cancer cells to platinum can develop by numerous mechanisms regulated by several genes. An individual miRNA negatively regulates dozens of distinct gene expression, thus it can be used as a suitable target for improving chemotherapeutics. We propose that some dysregulated miRNAs involve in recurrence of ovarian tumors by repressing dozens of gene expression. Here we show that miR-509-3p exhibits a decreased level in recurrent ovarian tumors compared to their primary pairs. Overexpressing miR-509-3p in ovarian cancer cells, SKOV-3, increases their sensitivity to platinum but not paclitaxel treatment. Decrease of endogenous miR-509-3p is also found in platinum-resistant A2780CP70 cells compared to their parental platinum-sensitive A2780 cells. Overexpression of miR-509-3p in A2780CP70 cells increases their sensitivity to platinum treatment. Undoubtedly, inhibition of miR-509-3p in A2780 cells, they become more resistant to platinum treatment. Transcriptome microarray analyses of miR-509-3p overexpression in A2780CP70 and SKOV-3 cells identify a potential target of miR-509-3p called phosphoglucomutase-1, PGM1, which may increase cells resistance to platinum. Overexpession of miR-509-3p reduces the expression level of PGM1. Silencing PGM1 in A2780CP70 cells leads to platinum sensitization. Taken together, here we report that miR-509-3p sensitizes ovarian cancer cells to platinum treatment by repressing the expression of PGM1, and miR-509-3p may have beneficial effects on ovarian cancer chemotherapeutics.

Contents
Abstract in Chinese ...................................................I
Abstract .................................................II
Acknowledgement ........................................ III
Contents...................................................V
Abbreviation ............................................XII
Introduction ..............................................1
1. General introduction of ovarian cancer .................1
2. Recurrence of ovarian cancer............................1
3. Mechanisms of platinum resistance.......................2
4. General introduction and biogenesis of microRNAs .......3
5. Post-transcriptional repression by miRNAs ..............5
6. MiRNAs and cancer ......................................6
Rational and Specific Aims.................................8
Materials and methods .....................................9
Reagents and Equipments ...................................9
1. Clinical specimens .....................................9
2. Stem-loop quantitative real-time PCR analysis for mature miRNAs (TaqMan miRNA assay) ...............................9
3. Cell Culture ..........................................10
4. Transfection of pre-miR mimics and miRNA inhibitor oligos....................................................10
5. Drug treatment ........................................11
6. MTS cell viability assay...............................11
7. Reverse transcription-polymerase chain reaction (RT-PCR) analysis .................................................11
8. Quantitative Real-time PCR (qRT-PCR) analysis..........12
9. Production and infection of recombinant lentiviral particles ................................................13
10. Western blot analysis ................................13
11. Construction of the pMIR-PGM1-3’ -UTR -luciferase plasmid...................................................14
A. Construction of yT&A- PGM1- WT-3’-UTR plasmid..........14
B. Transformation of yT&A- PGM1- WT-3’-UTR plasmid........15
C. Construction of pMIR-PGM1-WT-3’-UTR-luciferase plasmid 16
D. Construction of pMIR-PGM1-Mut.-3’-UTR-luciferase plasmid...................................................16
12. PGM1-3’-UTR Reporter Assays ..........................18
13. Statistical Analysis..................................18
Results...................................................19
1. Expression of miR-509-3p was down-regulated in recurrent ovarian tumors and cisplatin-resistant ovarian cancer cells. ...................................................19
2. miR-509-3p increased the platinum drug sensitivity in multi-drug resistant SKOV3 human ovarian adenocarcinoma cells.....................................................20
3. Modulation of platinum drug sensitivity by miR-509-3p in platinum-sensitive A2780 and platinum-resistant A2780CP70 cells.....................................................21
4. Identification of miR-509-3p targets contributed to platinum resistance in ovarian cancer cells...............22
5. miR-509-3p directly repressed the expression of PGM1...23
6. Overexpressing miR-509-3p promoted the cisplatin-induced apoptosis ................................................23
7. Expression of PGM1 in ovarian cancer specimens. .......24
Discussion................................................25
1. Clinical evidence of miR-509-3p in recurrence of ovarian cancer . .................................................25
2. Potential mechanism lead to the down-regulation of miR-509-3p in recurrent ovarian tumors........................25
3. Upstream regulation of miR-509-3p......................26
4. Does miR-509-3p contribute to metastasis of ovarian cancer?...................................................27
5. How does PGM1 regulate the platinum resistance of cancer cells? ...................................................27
6. The role of promyelocytic leukemia protein in miR-509-3p-mediated enhancement of platinum cytotoxicity.............28
7. The role of TWIST1 in miR-509-3p-mediated enhancement of platinum cytotoxicity.....................................29
8. Other potential targets of miR-509-3p may involve in platinum resistance ......................................29
9. Therapeutic potential of miR-509-3p combined with platinum drugs in ovarian cancer therapy..................30
Conclusion................................................32
Reference.................................................33
Curriculum Vitae..........................................63

Table contents
Table.....................................................41
Table 1. The clinicopathologic characteristics of the ovarian cancer specimens .................................41
Table 2. Sequences of shRNAs used in this study.*.........42
Table 3. Primers used in RT-PCR and qRT-PCR ..............43

Figure contents
Figure....................................................44
Figure 1. Expression profile of miR-509-3p in ovarian cancer tissues............................................44
Figure 2. The expression of miR-509-3p in primary and recurrent ovarian cancer tissues..........................45
Figure 3. The effects of platinum and paclitaxel treatments on the viability of SKOV3 ovarian cancer cells overexpressing miR-509-5p or miR-509-3p precursor mimics..46
Figure 4. Expressions of miR-509-3p and the effects of cisplatin treatment on viability in cisplatin-sensitive A2780 and cisplatin-resistant A2780CP70 cells. ...........47
Figure 5. Overexpression of miR-509-3p significantly increased platinum sensitivity in platinum-resistant A2780CP70 ovarian cancer cells. ..........................48
Figure 6. Inhibition of miR-509-3p reduced platinum sensitivity in platinum-sensitive A2780 ovarian cancer cells.....................................................49
Figure 7. Detection of miR-509-3p-mediated gene repression in A2780CP70 and SKOV3 ovarian cancer cells through global transcriptome microarray and bioinformatics...............50
Figure 8. Identification of potential miR-509-3p targets contributed to platinum resistance of A2780CP70 cells.....51
Figure 9. Regulation of phosphoglucomutase-1 (PGM1) by miR-509-3p in ovarian cancer cells............................52
Figure 10. Demonstration of directly repression of PGM1 by miR-509-3p in A2780CP70 ovarian cancer cells..............53
Figure 11. Overexpression of miR-509-3p increased the
apoptotic marker cleaved PARP expression after A2780CP70 cells treating with 15 μM cisplatin for 24 hours..........54
Figure 12. The expression of PGM1 in primary and recurrent ovarian cancer tissues....................................55
Figure 13. A diagram elucidated endogenous miR-509-3p modulated the viability of ovarian cancer cells to platinum drugs by directly repressing the expression of PGM1.......56


Appendix contents
Appendix .................................................57
Appendix 1. Construct map of pMIR-PGM1-WT-3’-UTR..........57
Appendix 2. Construct map of pMIR-PGM1-Mut.-3’-UTR........58
Appendix 3. pMIR-REPORT-Luciferase vector map.............59
Appendix 4. Reagents .....................................60
Appendix 5. Equipments....................................62


                                    

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