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系統識別號 U0026-2008201316000800
論文名稱(中文) 細胞自噬藉由正向調控miR-449a參與大腸直腸癌之致癌機轉
論文名稱(英文) An autophagy up-regulated microRNA miR-449a participates in the tumorigenesis of colorectal cancer
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 林紓晴
研究生(英文) Shu-Ching Lin
學號 S46001040
學位類別 碩士
語文別 英文
論文頁數 81頁
口試委員 指導教授-劉校生
口試委員-呂增宏
口試委員-謝式洲
口試委員-謝長奇
口試委員-陳百昇
中文關鍵字 細胞自噬  miR-449a  FoxO1  大腸直腸癌 
英文關鍵字 Autophagy  miR-449a  FoxO1  colorectal cancer 
學科別分類
中文摘要 細胞自噬是一種壓力引起的代謝過程,老化或損壞的胞器會被降解,並將能量重新釋出以維持細胞存活。細胞自噬在癌症進程中可抑制腫瘤發生,也可保護癌細胞免於受到飢餓所引發的凋亡。MicroRNAs (miRNAs) 是一種非編碼核之小片段RNA,可藉由和其標的mRNA的3'-UTR 片段結合直接將其RNA降解或抑制基因轉錄。MiRNA在腫瘤的生成中亦扮演雙重角色,然而其中詳細的機制尚未釐清。細胞自噬反應是否可能經由調控特定之微小RNA(miRNA)影響腫瘤之生成?經由microRNA microarray的搜尋找到和細胞自噬呈正相關的微小RNA-miR-449a。利用定量即時反轉錄聚合酶鏈鎖反應分析70對大腸直腸癌病人的檢體,發現miR-449a之表達量和大腸直腸癌的分期、轉移及復發呈負相關,且在接收操作特徵曲線分析中指出miR-449a是很有潛力做為大腸直腸癌分期及復發的生物標記。藉由誘導子amiodarone (原抗心律不整藥物)誘導大腸直腸癌SW480細胞之自噬反應可促進miR-449a表現。此外正常情況下,Forkhead轉錄因子家族中之FoxO1會被p300蛋白乙醯化而存在於細胞質中;細胞處於飢餓時,FoxO1則從細胞質中進入細胞核。進一步研究發現amiodarone誘導的自噬反應伴隨著p300表現下降,以及核內的FoxO1表現量顯著增加。我們在miR-449a之啟動子區域預測到數個FoxO1的結合序列。由此推論細胞自噬透過降解p300促使FoxO1入核,並啟動miR-449a啟動子的活化。CyclinD1和 LEF-1是miR-449a已知的標的基因。細胞株實驗發現增加miR-449a表現或以amiodarone誘導自噬反應均能透過抑制LEF-1及cyclinD1之表現進而影響SW480細胞的細胞週期進行、增殖、細胞群落形成、爬行及入侵能力。此外細胞自噬亦可不經miR-449a直接造成LEF-1和cyclinD1的表現下降。Amiodarone 誘發之自噬反應抑制腫瘤的生成在小鼠之腫瘤實驗中亦得到証實。此外利用原位雜合及免疫組織化學染色法技術分析在小鼠腫瘤及18對大腸直腸癌tissue array中發現在腫瘤部分的miR-449a 以及細胞自噬相關基因Beclin 1表現量均明顯下降,相對的p62、LEF-1以及cyclinD1的表現量在腫瘤部分中則明顯較高。綜述之,本研究為第一篇報導細胞自噬所誘導的miR-449a會抑制大腸直腸癌發生。其機轉可能經由FoxO1入核促進miR-449a的基因轉譯。且其和大腸直腸癌中LEF-1、cylinD1表現量、復發及轉移的病人呈負相關。此外amiodarone是一個相當具有潛力用來預防及治療大腸直腸癌的藥物。
英文摘要 Autophagy is a stress-induced catabolic process to degrade organelles, proteins and to release energy for maintaining cell survival. Autophagy either suppresses tumor formation or prevents cancer cells from starvation-related death. MicroRNAs (miRNAs) are small none coding RNAs, which bind to the 3'-UTR region of the target gene and cause degradation of mRNA or inhibition of translation. MiRNAs also play critical roles during cancer formation. However, the underlying mechanism remains elusive. We hypothesize that autophagy may affect tumorigenesis through regulation of miRNAs. We previously identified an autophagy up-regulated miRNA miR-449a by miRNA microarray. MiR-449a expression is inversely correlated with stages, metastasis status and recurrence in seventy paired colorectal cancer (CRC) specimens by real-time polymerase chain reaction. Receiver operating characteristics (ROC) analysis indicated that miR-449a was a potential biomarker for CRC stage and recurrence. Our data showed that amiodarone (an antiarrhythmic drug) induced-autophagy up-regulates miR-449a expression in CRC SW480 cells. Under autophagic induction conditions, forkhead transcription factor family member FoxO1 is transported from the cytoplasm to the nucleus. Under normal conditions, FoxO1 is acetylated by the coactivator protein p300 and located in the cytoplasm. Under amiodarone-induced autophagic conditions, the expression of p300 was inhibited and the amount of FoxO1 in nucleus was increased. Furthermore, multiple FoxO1 binding sites in the miR-449a promoter region were predicated. Therefore, autophagy may promote miR-449a expression though degradation of p300 followed by the translocation of FoxO1 into the nucleus. CyclinD1 and LEF-1 are the known target genes of miR-449a. We revealed that either miR-449a over-expression or amiodarone-induced autophagy inhibits cycle progression, proliferation, colony formation migration and invasion of SW480 cells though inhibiting LEF-1 and cyclinD1 expression in vitro. We also demonstrated that autophagy may suppress the protein expression of LEF-1 and cyclinD1 in a miR-449a independent manner. Moreover, amiodarone inhibits mice tumor formation in vivo. The mice tumors and a tissue array consisting of 18 paired CRC specimens were analyzed by ISH and IHC. Our data showed that miR-449a and autophagy related gene Beclin 1 expression was low in the tumor parts. In contrast, the expression of p62 and miR-449a target gene, LEF-1 and cyclinD1 was high in the tumors. In summary, this is the first report to reveal that an amiodarone-induced autophagy leads to miR-449a up-regulation. Autophagy up-regulation of miR-449a was at the transcriptional level through FoxO1. MiR-449a expression is inversely correlated with the expression of LEF-1 and cyclinD1 as well as the recurrence and metastasis of CRC patients. Our findings indicate that amiodarone may have the potential to be used for prevention and treatment of CRC.
論文目次 Index
中文摘要 I
Abstract III
Acknowledgements V
Index VI
Table and Figure List IX
Abbreviation X
Introduction
I. Autophagy 1
II. Autophagy and tumorigenesis 2
III. MicroRNA 3
IV. MicroRNA and tumorigenesis 4
V. The relationship between autophagy and miRNA 5
VI. Colorectal cancer (CRC) 6
VII. The relationship among autophagy, miRNA and CRC 6
Materials and Methods
I. Cell lines and cell culture 8
II. Tissue specimens 8
III. Quantitative real-time PCR (qRT-PCR) 9
IV. Western blot analysis 10
V. Immunofluorescent staining 10
VI. DNA constructs 11
VII. Luciferase reporter assay 11
VIII. Cell viability analysis 12
IX. BrdU incorporation assay 12
X. Cell cycle analysis 12
XI. Colony formation 13
XII. Cell migration and invasion assay 13
XIII. Transient transfection of cells with miRNA 14
XIV. Xenografted tumor mice model 14
XV. Immunoprecipitation assay 15
XVI. Immunohistochemistry (IHC) 15
XVII. In-situ hybridization (ISH) 16
XVIII. Statistical analysis 17
Results
I. Screening for autophagy and tumorigenesis related miRNA 18
II. Amiodarone-induced autophagy regulates the expression of miR-449a in SW480 cells 18
III. The mechanism of autophagy up-regulated miR-449a 19
IV. Low expression of miR-449a in CRC specimens 20
V. MiR-449a inhibits the growth of colon cancer SW480 cells 21
VI. MiR-449a inhibits the migration and invasion of SW480 cells 22
VII. MiR-449a inhibits its target gene LEF-1 and cyclinD1 in SW480 cells 22
VIII. Amiodarone-induced autophagy suppresses the tumorigenesis of CRC in vitro. 23
IX. Autophagy suppresses target genes in a miR-449a independent manner. 24
X. Amiodarone-induced autophagy inhibits the tumor growth of CRC in vivo. 25
XI. Clinical relevance of miR-449a and Beclin 1 down-expression to FoxO1, autophagy, LEF-1 and cyclinD1 in human CRC 26
Discussion 27
References 34
Curriculum Vitae 81
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