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研究生：	楊于嬋 Yang, Yu-Chan
論文名稱：	MiR-449a在細胞自噬和Ras致癌基因相關腫瘤形成之角色 The role of miR-449a in autophagy and Ras oncogene related tumorigenesis
指導教授：	劉校生 Liu, Hsiao-Sheng
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	75
中文關鍵詞：	細胞自噬、miRNA 、腫瘤形成、Ha-ras 、miR-449a
外文關鍵詞：	autophagy, miRNA, tumorigenesis, Ha-ras, miR-449a
相關次數：	點閱：76 下載：0
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細胞自噬(Autophagy)在許多正常生理及疾病過程中扮演重要角色，包含老化、神經退化、及腫瘤生成。Ha-ras 為一種致癌基因，其可以誘發細胞自噬並誘發腫瘤發生。MicroRNAs (miRNAs)是一群非編碼的小RNAs，藉由轉譯的降解或抑制轉錄來抑制目標基因的表現。細胞自噬與miRNAs皆與腫瘤形成有關，然而目前三者之間的關係及作用機制仍不清楚。我們之前的研究發現，在NOD/SCID 小鼠中，細胞自噬缺失與野生型的小鼠胚胎纖維母細胞中(MEF)比較，若前者高量表現突變的Ha-ras致癌基因，會誘發較大的腫瘤生成。因此，細胞自噬在ras相關腫瘤生成過程中扮演抑制的角色。本篇研究探討細胞自噬是否誘導某些miRNAs表現量增加而抑制腫瘤發生。我們利用誘導或抑制細胞自噬的方式篩選，挑選出細胞自噬正向調控的miR-449a。透過pyrosequencing偵測，甲基化不會影響miR-449a的表現，因此，miR-449a在轉錄(transcription)階段可能透過其他機制來調控。In vitro實驗中証實miR-449a可抑制細胞移動與細胞群落的生長。進一步在NOD/SCID小鼠模式中証實miR-449a具有抑制腫瘤生長的能力。而由三個軟體Targetscan，miRBase和picTar預測相互比對得出，可能與腫瘤形成有關的miR-449a標的基因，透過mRNA的分析，Lef1可能是miR-449a的標的基因。因此，在細胞自噬下miR-449a會被正向調控，進而抑制腫瘤生成。透過本篇研究，miR-449a可能成為腫瘤治療上的一個標的。

Autophagy plays an important role in pathophysiologic process including aging, neuronal degeneration, and tumorigenesis. Ha-ras, an oncogene, can induce autophagy and promote tumorigenesis. MicroRNAs (miRNAs), a group of non-coding RNAs, suppress target-mRNA expression either by transcriptional degradation or by translational inhibition. Autophagy and miRNAs are all involved in tumorigenesis, however, the relationship among them is still unclear. We previously showed that overexpression of mutant Ha-ras oncogene in autophagy deficient mouse embryo fibroblast (MEF) cells induces larger tumor formation compared with wild-type MEF cells in NOD/SCID mice, indicating that autophagy plays a suppressive role in Ras-related tumor formation. In this study, we are interested in whether autophagy inhibits tumorigenesis through up-regulation of miRNAs. Autophagy-related miRNAs was identified by autophagy inducers and inhibitors. Among them, miR-449a was significantly up-regulated under autophagic conditions. Our data showed that methylation does not affect miR-449a expression by pyrosequncing indicating other mechanism(s) is responsible for the regulation miR-449a at transcriptional level. Furthermore, cell migration and colony formation were significantly inhibited when miR-449a was overexpressed. We further demonstrated that miR-449a played a suppressive role in tumor formation under autophagic condition in NOD/SCID model. Tumorigenesis-related genes were identified by overlapping the target genes of three software including miRBase, picTar, and Targetscan, and Lef1 may be the miR-449a target based on mRNA expression. Together, autophagy regulates miR-449a expression at transcriptional level to suppress tumorigenesis. These finding suggest that miR449a may be a marker toward cancer therapy.

中文摘要 I
Abstract III
誌謝 V
Abbreviations X
Introduction
I. Autophagy 1
II. Autophagy and tumor formation 1
III. MiRNA and tumor formation 2
IV. MiRNAs regulation 3
V. Ras oncogene 3
VI. Autophagy, miRNA and tumorigenesis 4
Materials and Methods
I. Cell lines and cell culture 6
II. Autophagy induction 6
III. Lentiviral shRNA experiments 7
IV. Immunoblotting analysis 8
V. Quantitative real-time PCR (qRT-PCR) 9
VI. Polymerase chain reaction (PCR 9
VII. 5-Aza-2’-deoxycytidine (5-Aza-dc) treatment 10
VIII. Genomic DNA extraction and DNA bisulfited 10
IX. Pyro-PCR and Pyrosequencing assay for miR-449a promoter region methylation 10
X. pMIR-reporter vectors and DNA constructs 11
XI. Large amount plasmid preparation 12
XII. Luciferase reporter assay 13
XIII. Transient transfection of cells with pre-miR-449a 13
XIV. Transwell migration assay 14
XV. Colony formation 14
XVI. Mice model 14
XVII. MiRNA target gene predication 15
XVIII. Statistical analysis 15
Results
I. Autophagy-related miRNAs are validated by real-time PCR 16
II.	MiRNA expression in MR cells is evaluated under Ha-ras, rapamycin, or HBSS treatments 17
III. K-ras induces autophagy and miR-449a overexpression 18
IV. MiR-449a expression is regulated at transcriptional level under the condition of ras overexpression induced autophagy 19
V. Methylation does not affect miR-449a promoter activity under the conditions of induced autophagy 19
VI. Specific suppression of miR-449a on pMIR-reporter luciferase    activity carrying miR-449a precursor sequence is confirmed by luciferase activity assay 20
VII. MiR-449a plays a suppressive role in tumorigenesis 21
VIII. Target genes of miR-449a are verified by mRNA expression 22
Discussion 23
References 26
Table and Figure List
Table 1 The sequence of Atg5 (TRCN0000099430)-specific shRNA used in the lentiviral system 34
Table 2 The information of antibodies used in this study 35
Table 3 The primers used in this study 36
Table 4 Up- and down-regulated miRNAs in M5R and MR cell lines 40
Table 5 The expression of five miRNAs under various autophagic stimulation and inhibition 41
Table 6 The potential target genes of miR-449a 42
Table 7 The potential tumorigenesis-related targets of miR-449a 45
Figure 1 Validation of the correlation of five miRNAs with autophagy   by qRT-PCR and lentiviral system 46
Figure 2 Ha-ras, rapamycin or HBSS-induced autophagy regulates miRNAs expression 48
Figure 3 K-ras induces autophagy and miR-449a overexpression 51
Figure 4 Autophagy affects miR-449a at transcriptional level demonstrated by real-time PCR 53
Figure 5 Methylation does not affect miR-449a expression under autophagic conditions 55
Figure 6 MiR-449a specifically suppresses the luciferase activity of pMIR-reporter plasmid harboring wild type miR-449a precursor binding sequence 58
Figure 7 MiR-449a inhibits cell migration and colony formation demonstrated by Transwell migration assay and soft agar analysis 60
Figure 8 MiR-449a inhibits tumorigenesis in vivo 63
Figure 9 The mRNA expression of miR-449a potential target           genes 67
Appendix List
Appendix 1 Ras inducible system 70
Appendix 2 Autophagy regulation 71
Appendix 3 Plasmid pMD.2G and psPAX2 for lentiviral production 72
Appendix 4 The Pyrosequencing cascade system and quantitative analysis of CpG methylation 73
Appendix 5 pMIR-reporter luciferase plasmid for pMIR-reporter construction 74
Curriculum Vitae 75

                                    

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校內：2013-09-02公開
校外：不公開電子論文尚未授權公開，紙本請查館藏目錄

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