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研究生：	賴輝寰 Lai, Hui-Huang
論文名稱：	缺氧誘發因子-1α藉由誘導Dicer蛋白質降解抑制微小核醣核酸生合成促進癌症轉移 HIF-1α-induced Dicer proteolysis suppresses miRNA biogenesis to promote cancer metastasis
指導教授：	陳百昇 Chen, Pai-Sheng
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	134
中文關鍵詞：	Dicer 、缺氧誘發因子-1α 、細胞自噬、癌症轉移、微小核醣核酸-200b
外文關鍵詞：	Dicer, HIF-1α, autophagy, cancer metastasis, miR-200b
相關次數：	點閱：74 下載：3
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微小核醣核酸是需多重步驟的處理而產生的，並且能夠抑制目標基因轉錄的表現。微小核醣核酸的失調已被證實與人類癌症有關。Dicer是一個主要調控微小核醣核酸生合成的酵素，能夠在RNA誘導沉默複合體(RISC)中將微小核醣核酸前驅物切割成微小核醣核酸進而抑制目標基因表現。在動物實驗中被證明去除Dicer的表現能增強腫瘤新生，因此Dicer被認為具有抑制腫瘤的功能。根據這樣的概念，Dicer在不同種腫瘤組織中發現皆有表現量下降的現象並能夠藉由抑制微小核醣核酸的生合成促進癌症轉移及腫瘤新生，但是以目前的知識對於抑制微小核醣核酸的上游調控者還是尚未清楚的。缺氧誘發因子-1α (HIF-1α)是一個充分被研究的一種轉錄因子，會在缺氧環境及生長因子刺激下被活化，促進癌症發展。在本篇研究中，我們在不同種癌細胞及人類腫瘤組織中證明於微小核醣核酸生合成中的關鍵酵素Dicer是HIF-1α的一個新結合蛋白。在癌細胞中HIF-1α表現量增加會降解蛋白質Dicer表現進而抑制解微小核醣核酸生合成。腫瘤微環境誘導的HIF-1α表現會連結Dicer與E3泛素連接酶Parkin 的結合，這樣的結合會促使Dicer泛素化並被細胞自噬受器p62所辨認進入到細胞自噬-溶體系統進行蛋白質降解。Dicer的下降會降低let-7b與miR-200b的生合成達到促進ZEB1所調控的上皮-間質細胞轉換與癌症轉移。本研究為首次證明Dicer是HIF-1α新結合蛋白，並促進Dicer進入細胞自噬-溶體系統進行蛋白質降解。這些發現可以提供一個Dicer被抑制的新穎機轉是透過HIF-1α非轉譯的功能，這樣的結果也證實了HIF-1α一個非典型的致癌作用。

MicroRNA (miRNA) is generated by multiple steps processing that post-transcriptionally suppress the expression of target genes. Dysregulation of miRNAs has been implicated in human cancer malignancy. Dicer, a central enzyme conducts miRNA precursors into the RNA-induced silencing complex (RISC) to process mature miRNA for a post-transcriptional gene silencing. In mouse model, deletion of Dicer expression enhanced tumorigenesis, functioning as a haploinsufficient tumor suppressor. Supporting to this concept, downregulation of Dicer expression was observed in multiple human tumors and has been supposed to promote cancer metastasis and tumorigenesis due to repression of global miRNA maturation but the origin of this mechanism is not well understood. Hypoxia-inducible factor-1α (HIF-1α) is a well-studied transcription factor activated by tumor microenvironment for cancer development, including hypoxic condition and growth factors stimulation. Here we identify a critical miRNA processing enzyme, Dicer that is a novel HIF-1α interacting protein in multiple cancer cells and human tumor tissues. HIF-1α post-translationally degrades Dicer protein to attenuate miRNA biogenesis in cancer cells. Microenvironmental stimulation-induced HIF-1α bridges and enhances the binding of Dicer and Parkin. This interaction further ubiquitinates Dicer to be recognized by autophagic receptor p62 for autophagic-lysosomal degradation. Subsequently, downregulation of Dicer reduces maturation of let-7b and miR-200b to facilitate ZEB1-mediated EMT and cancer metastasis. The present study first identifies Dicer as a novel HIF-1α-targeting protein for autophagic-lysosomal proteolysis of Dicer. These findings provide a novel mechanism of Dicer downregulation through a HIF-1α transcription independent function that exerts an unconventional oncogenic effect of HIF-1α.

中文摘要.................................................I
Abstract...............................................II
致謝..................................................III
Contents................................................V
List of figures........................................IX
List of tables.......................................XIII
List of appendixes....................................XIV
Abbreviations..........................................XV

Chapter 1 - Introduction................................1
A. Cancer..................................................1
A-1. Cancer initiation..................................1
A-2. Transcription factor...............................1
B. Cancer metastasis....................................2
B-1. Cancer metastatic process..........................2
B-2. Metastasis in TNM system...........................3
C. Epithelial-mesenchymal transition....................3
C-1. The processes of EMT...............................3
C-2. Induction of EMT...................................4
D. Colorectal cancer....................................5
D-1. The incidence of CRC...............................5
D-2. The mortality of CRC...............................6
E. Hypoxic condition....................................6
E-1. Tissue hypoxia.....................................6
E-2. Hypoxia-inducible factors-1α.......................7
F. MicroRNA.............................................8
F-1. MircoRNA biogenesis................................8
F-2. MircoRNA biogenesis factors........................9
G. Downregulation of Dicer in cancer...................10
G-1 Dicer..............................................10
G-2. Modification of Dicer protein.....................11
G-3. The role of Dicer in cancer.......................11
H. Ubiquitin...........................................12
H-1. The Ubiquitin system..............................12
H-2. Targeting ubiquitin system in cancer..............13
I. Autophagy...........................................14
I-1. Formation of autophagosome........................14
I-2. Classification of autophagy.......................14

Chapter 2 - Specific aims..............................16

Chapter 3 - Materials and Methods......................18
3.1 Cell culture.......................................18
3.2 Immunoprecipitation assay..........................18
3.3 Constructs.........................................19
3.4 Lentiviral knockdown...............................20
3.5 Human subjects.....................................20
3.6 In vivo metastasis studies.........................20
3.7 Metastasis animal experiments......................21
3.8 Western blot analysis..............................21
3.9 Mass spectrometry..................................22
3.10 Confocal microscopy analysis......................22
3.11 Autophagosome isolation...........................23
3.12 Boyden chamber migration assay....................23
3.13 Isolation of RNA and reverse transcription real-time PCR....................................................24
3.14 Statistical analysis..............................24
3.15 Study approval....................................25

Chapter 4 - Results....................................26
4.1 HIF-1α directly interacts with Dicer in tumor tissues and multiple cancer cell lines.........................26
4.2 HIF-1α suppresses Dicer protein expression in response to hypoxic and non-hypoxic activators.........27
4.3 HIF-1α transcription independently facilitates Dicer protein degradation through autophagic-lysosomal pathway	.......................................................29
4.4 HIF-1α recruits association of Dicer and Parkin E3 ligase that facilitates Dicer ubiquitination for a signal of selective autophagy.................................31
4.5 Identification of functional domains of HIF-1α-Dicer interaction............................................33
4.6 HIF-1α-mediated Dicer downregulation inhibits miRNA maturation and targeting inhibition....................34
4.7 HIF-1α-induced miR-200b suppression promotes EMT of cancer cells...........................................36
4.8 HIF-1α-induced miR-200b suppression promotes lung-metastatic colonization................................37
4.9 HIF-1α-induced miR-200b suppression facilitates cancer metastasis......................................38

Chapter 5 - Discussion.................................40
5.1 The regulators alters miRNA biogenesis.............40
5.2 The ubiquitination of Dicer........................40
5.3 Dual roles of Parkin in cancer.....................41
5.4 The role of Dicer in tumorigenesis.................42
5.5 Dicer plays as a scapegoat in HIF-1α-mediated cancer progression?...........................................43
5.6 Stabilized HIF-1α in regulation of Dicer...........44
5.7 HIF-1α-dependent and -independent mechanisms in suppression of Dicer...................................45
5.8 RNAi therapy.......................................46
5.9 Interference of interaction of HIF-1α and Parkin as a therapeutic strategy...................................48

Conclusion.............................................50

References.............................................51

Figures................................................69

Tables................................................123

Appendixes............................................127

Personal information..................................133

                                    

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