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系統識別號 U0026-1310201312543200
論文名稱(中文) miR-224在細胞自噬與腫瘤形成中所扮演之角色
論文名稱(英文) Characterization of miR-224 and its involvement in autophagy and tumorigenesis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 1
出版年 102
研究生(中文) 藍昇輝
研究生(英文) Sheng-Hui Lan
學號 s58961248
學位類別 博士
語文別 中文
論文頁數 84頁
口試委員 指導教授-劉校生
召集委員-王憶卿
口試委員-賴明德
口試委員-周楠華
口試委員-黃偉邦
口試委員-洪文俊
中文關鍵字 細胞自噬  微小RNA  肝癌 
英文關鍵字 Autophagy  microRNA  HCC 
學科別分類
中文摘要 在形成肝癌之過程中,已經分別的證實了會發生細胞自噬能力之缺失以及微小RNA-224高量表達之現象。然而,它們三者之間是否有關聯性仍然是不清楚的。在此研究中,我們了發現了不論是在HBV之X基因轉殖鼠還是在HBV的肝癌病人檢體當中,細胞自噬能力的確是下降的,並且與微小RNA-224呈現負相關。除此之外,為了了解細胞自噬現象是如何調控微小RNA-224;我們將細胞中之自噬小體純化出來,並且利用即時聚合連鎖反應以及電顯原位雜交之技術,證實細胞自噬發生之過程,會選擇性的將微小RNA-224包裹並分解掉。在我們的體外實驗中也證實了微小RNA-224在肝癌細胞的細胞移動能力與腫瘤形成過程中,藉由抑制其標的基因smad4而扮演著促進癌症的角色。由病人資料分析後發現,細胞自噬能力下降,微小RNA-224高量表達,以及smad4表現量下降;這些現象都顯著與HBV感染有關。並且,符合這三者之病人,其術後存活率則是明顯下降。此外,我們建立了肝癌原位癌之大鼠動物模式,並利用細胞自噬誘發劑(amiodarone)以及微小RNA-224之互補序列,分別藉由細胞自噬降解以及直接抑制微小RNA-224之表現量,其結果皆可有效抑制肝癌之形成。此外,我們在大腸癌的臨床檢體中也觀察到細胞自噬能力下降。在大腸癌的研究中,我們發現細胞自噬現象可以正向調控另一個微小RNA: 微小RNA-X。其可能之機制為細胞自噬藉由促進微小RNA-X之轉錄生成增加。經由細胞自噬所生成的微小RNA-X,會抑制其標的基因,並有效的抑制大腸癌細胞之生長,爬行,侵襲與腫瘤形成之相關能力。我們在大腸癌組織晶片中印證了此新機制,細胞自噬能力下降,微小RNA-X表現量下降,而其標的致癌基因則大量表現在腫瘤組織中。綜述之,細胞自噬可以藉由直接降解微小RNA-224以及促進微小RNA-X轉譯來調控微小RNA之表現量。而在HBV相關的肝癌與大腸癌之癌化過程,由於細胞自噬能力之下降,進而導致其微小RNA與其標的基因之異常表現而促進癌症發生。而此研究也將開啟對於HBV相關肝癌與大腸癌之新的治療方向。
英文摘要 In hepatocellular carcinoma (HCC) tumorigenensis, microRNA-224 (miR-224) overexpression or autophagy deficiency has been reported. However, the relationship between them has not been explored. Here we disclose that autophagic level was down-regulated and inversely correlated with miR-224 expression in HBV-associated HCC patient specimens. These results were confirmed in the liver tumor of HBV X gene (HBx)-transgenic mice. Furthermore, miR-224 was selectively recruited and degraded during autophagic progression demonstrated by real-time PCR and in situ hybridization electron microscopy (ISH-EM) after extraction of autophagosomes. Our in vitro study showed that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. The HCC patients with low-Atg5, high-miR-224 and low-Smad4 expression showed significant correlation with HBV infection and poor overall survival rate. Autophagy mediated miR-224 degradation and suppression of liver tumor formation was further confirmed using the autophagy inducer amiodarone and anti-miR-224 in the orthotopic rat model. Furthermore, low autophagy activity was also detected in colorectal cancer (CRC) specimens. Differently, autophagy up-regulates another miRNA, miR-X, through a transcriptional regulation pathway. Autophagy-induced miR-X suppressed the expression of target genes expression and played tumor suppressive role including suppression cell proliferation, migration, invasion and tumor formation of CRC both in vitro and in vivo. We further revealed the relationship among autophagy, miR-X, and it’s target genes by CRC tissue array. In summary, we reveal a non-canonical pathway by which autophagy regulates miRNAs expression through directly degrading miR-224 and promoting transcription of miR-X. In HBV-associated HCC and CRC, autophagy deficiency causes dysregulation of miRNAs and their target genes, which are responsible for promotion of tumorigenesis. Our novel findings open a new avenue for the treatment of HBV-related HCC and CRC.
論文目次 Contents
Abstract I
Chinese Abstract .III
Acknowledgments .V
Contents VIII
Table contents XI
Figure contents XII
Abbreviation list XV
Chapter 1 Introduction 1
1.1 Ras oncogene 1
1.2 Hepatocellular carcinoma (HCC) 2
1.3 Autophagy and HCC 3
1.4 microRNAs and HCC 4
1.5 Autophagy and micRNA 5
1.6 Autophagy, miRNA and tumorigenesis 5
1.7 Specific aim 6
Chapter 2 Materials and Methods 7
2.1 Cell lines and reagents 7
2.2 Western blot analysis 7
2.3 MicroRNA Microarray analysis 8
2.4 Transwell assay for cell migration 8
2.5 miRNA target gene predication 9
2.6 Assay for the activity of miRNA luciferase reporter plasmid 9
2.7 Immunohistochemistry staining (IHC) staining 10
2.8 Cell transfection and RNA interference 10
2.9 MiRNA in situ hybridization (miRNA ISH) 10
2.10 Fluorescent miRNA ISH and immunofluorescence staining 11
2.11 Transmission electronic microscopy (TEM) 12
2.12 Autophagosome extraction 12
2.13 MiRNA ISH- electron microscopy 13
2.14 Mice and tumors 13
2.15 Orthotopic rat model of liver tumor formation 14
2.16 HBV X gene (HBx) transgenic mice 14
2.17 Detection of miRNA and message RNA expression by real-time polymerase chainreaction (PCR) 15
2.18 Detection of virus gene by reverse transcription-PCR and reverse transcription- nested PCR 15
2.19 Clinical specimen and verification 16
2.20 Statistical analysis 16
Chapter 3 Results 17
3.1 The level of autophagy is inversely correlated with miR-224 expression in autophagy deficiency cell lines and tumors 17
3.2 The level of autophagy is inversely correlated with miR-224 expression in HBV-associated HCC 18
3.3 Low level of autophagy and high miR-224 expression is detected in the liver tumors of HBx-trangenic mice 19
3.4 Mature miR-224 is preferentially recruited and degraded through the autophagosome-lysosome pathway 19
3.5 The miR-224 is preferentially accumulated in the autophagosomes. 22
3.6 MiR-224 promotes tumorigenesis through silencing its target gene Smad4 22
3.7 Liver tumor formation is suppressed by manipulation of autophagic activity or miR-224 expression 24
Chapter 4 Discussion 26
Chapter 5 Autophagy suppresses tumorigenesis of colorectal carcinoma through promoting miR-X expression 32
Chapter 6 Conclusions 33
References 34
Tables 43
Figures 47
Appendix 77
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