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系統識別號 U0026-0307201403341300
論文名稱(中文) 人類C型肝炎病毒核鞘蛋白有調控hsa-Let-7b, hsa-miR-122, hsa-miR-199及hsa-miR-198的角色
論文名稱(英文) The human hepatitis c virus (HCV) core protein has a role in modulating hsa-Let-7b, hsa-miR-122, hsa-miR-199 and hsa-miR-198
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 蔡易達
研究生(英文) Yi-Ta Tsai
學號 T16001079
學位類別 碩士
語文別 中文
論文頁數 42頁
口試委員 指導教授-王憲威
口試委員-鄧景浩
口試委員-橋本昌征
中文關鍵字 C型肝炎病毒  核鞘蛋白  微小核醣核酸  hsa-miR-122  hsa-miR-198  hsa-miR-199  hsa-Let-7b 
英文關鍵字 HCV  HCVcore  MicroRNA  hsa-miR-122  hsa-miR-198  hsa-miR-199  hsa-Let-7b 
學科別分類
中文摘要 C型肝炎病毒 (Hepatitis C virus, HCV)屬於黃熱病毒科 (Flaviviridae),為具套膜 (envelope)的核醣核酸病毒 (RNA virus)。C型肝炎病毒感染主要引起急、慢性肝炎,慢性感染則會引起肝損傷、肝硬化,最後導致肝癌。微小核醣核酸 (MicroRNA)屬於一種短片段、未轉譯之核醣核酸。微小核醣核酸被指出參與細胞內諸多調節機制,不僅可能調控訊息傳遞而參與細胞癌化 (tumorigenesis),也可能扮演細胞對抗外來微生物或病毒的一種機制。HCV核鞘蛋白 (HCVcore protein)屬於病毒結構性蛋白 (structural protein)。文獻指出核鞘蛋白會與細胞因子作用而影響病毒感染,在細胞癌化中也扮演重要角色。我們的實驗室所發表的文獻指出核鞘蛋白會與hNRNPH1和NF45結合。hnRNPH1和NF45皆為RNA結合蛋白 (RNA binding protein)。另外,已知hnRNPH1會與DGCR8 (DiGeorge critical region 8)結合,而NF45會與NF90結合,而這些細胞蛋白因子皆在mRNA或抑制性RNAi的代謝生合成中扮演重要的角色。目前已知Dicer在微小核醣核酸作用機制中扮演重要角色,且亦有報告間接指出核鞘蛋白會與Dicer作用而可能影響核醣核酸沉默作用 (RNA silencing)。這些線索充分顯示核鞘蛋白可能會藉由影響微小核醣核酸作用機制,而調控C型肝炎病毒的感染和致癌性。近期文獻指出hsa-mir-122對於C型肝炎病毒感染為正向調控角色;hsa-let-7b和hsa-mir-199對HCV的感染 (infectivity)和複製 (replication)各扮演負向調控角色; hsa-mir-122、hsa-mir-199和hsa-mir-198對於C型肝炎病毒相關肝癌 (HCV related hepatocellular carcinoma)生長 (growth)或轉移 (metastasis)扮演負向調控角色。過度表達 (overexpression)hsa-mir-122會促進HCV的複製和感染,過度表達hsa-mir-199和hsa-let-7b則會抑制HCV的複製和感染。再者,HCV的感染也會使細胞內生性hsa-mir-122表現量被調升,而內生性hsa-let-7b表現量則被調降。由此可推論HCV會藉由調控內生性 (endogenous)微小核醣核酸的表現量來塑造宿主細胞內有利於病毒複製和感染的環境,但實際透過何種機制目前仍不十分清楚。因核鞘蛋白已知會與多種微小核醣核酸作用機制的成員作用,我們因此想探討核鞘蛋白是否影響細胞內微小核醣核酸 (hsa-mir-122、hsa-let-7b、hsa-mir-199和hsa-mir-198)的表現量,以便加以驗證核鞘蛋白是否在HCV感染時具有影響內生性微小核醣核酸的角色。我們以定量即時聚合酶鏈式反應 (qPCR)比較在有無C型肝炎病毒複製的肝細胞中 (Huh7.5和Huh7.5-FGR (HCV full-genome replicon)),結果顯示FGR感染的Huh7.5中,hsa-mir-122、hsa-mir-199和hsa-mir-198表現量較非感染的Huh7.5高,hsa-let-7b則較低。在此,hsa-mir-122和hsa-let-7b的結果與先前的文獻結果相符,顯示我們實驗的可信度。此外,我們第一次指出在HCV感染時內生性hsa-mir-199和hsa-mir-198的表現量會被調高。接著,我們發現與缺乏結構性蛋白的HCV複製子之細胞中 (SGR, HCV sub-genomic replicon)相比,在具有結構性蛋白的FGR感染的Huh7.5細胞中,hsa-let-7b被調升,而hsa-mir-122、hsa-mir-199和hsa-mir-198被調降。這個結果指出結構性蛋白 (HCVcore、Envelope protein 1和Envelope protein 2)具有影響內生性微小核醣核酸的角色。為了更進一步釐清核鞘蛋白對調控內生性微小核醣核酸表現量的角色,我們比較有無異位表達 (ectopic expression)核鞘蛋白之SGR感染的Huh7.5細胞的內生性微小核醣核酸表現量,結果顯示核鞘蛋白存在會使hsa-mir-122、hsa-let-7b、hsa-mir-199和hsa-mir-198的表現量皆較上升。上述結果顯示核鞘蛋白具有會調控受感染細胞內微小核醣核酸表現量的角色。統而言之,我們的研究在此指出核鞘蛋白會利用微小核醣核酸相關機制以影響受感染細胞內生性微小核醣核酸表現量,來應對宿主細胞抗病毒之防禦或調控細胞內病毒感染的環境,類同於許多哺乳類的病毒 (mammalian viruses)利用病毒蛋白或RNA分子作為RNA silencing suppressor (RSS)的機制來應對宿主細胞。未來,我們期望可利用此建立的細胞株模型與qPCR定量法更深入探討核鞘蛋白是否會藉由調控特定的,與微小核醣核酸processor (microRNA processor)及核鞘蛋白複合體伴隨的微小核醣核酸,而造成慢性病毒感染或細胞癌化。
英文摘要 Summary
The hepatitis C virus (HCV) core protein (HCVcore) constitutes the viral nucleocapsid structure, and is involved in viral persistence and pathogenesis possibly by interacting with host factors to modulate viral replication and cellular function. It is known that Dicer is an important component of microRNA processor, and HCVcore is associated with Dicer. These pieces of evidence suggest that HCVcore may modulate microRNA biogenesis or metabolism to regulate HCV infection and tumorigenesis. Because HCVcore may interact with many critical components of microRNA processing complexes, we ask in this study whether the levels of certain microRNAs (i.e., hsa-mir-122, hsa-let-7b, hsa-mir-199 and hsa-mir-198) would be affected by the presence of HCVcore in a Huh7.5 cell lines with replicating HCV. Firstly, we compared the 4 endogenous microRNA levels between Huh7.5 with or without replicating FGR (HCV full-genome replicon) by qPCR. The patterns of hsa-mir-122 and hsa-let-7b expression levels in cells with or without FGR are consistent with others in previous literatures, suggesting that our quantitation methods are reliable. Yet we first point out that HCV infection would increase expression of hsa-mir-199 and hsa-mir-198. Secondly, our result indicated that the structural proteins have roles in the modulation of endogenous microRNA. Finally, our result showed that the presence of HCVcore increases the expression level of hsa-mir-122, hsa-let-7b, hsa-mir-199 and hsa-mir-198. Collectively, our results indicated that HCVcore has an essential role in modulating microRNAs during HCV infection.


Keyword: HCV, HCVcore, MicroRNA, hsa-miR-122, hsa-miR-198, hsa-miR-199, hsa-Let-7b
論文目次 壹、 中文摘要…………Ⅱ
貳、 Abstract…………Ⅳ
參、 誌謝………………Ⅶ
肆、 目錄………………Ⅷ
伍、 表目錄……………Ⅹ
陸、 圖目錄……………ⅩⅠ
柒、 附錄目錄…………ⅩⅡ
捌、 縮寫表……………ⅩⅢ
玖、 序論
壹、 C型肝炎病毒………………1
1. HCV流行病學………………1
2. HCV簡介……………………2
3. HCV非結構性蛋白 (non-structure protein, NS)………2
4. HCV結構性蛋白 (structure protein)……………………4
貳、 微小核醣核酸 (MicroRNA)…………………………………6
1. MicroRNA歷史和簡介………………………………………6
2. MicroRNA生成機制………………………………………6
3. MicroRNA作用機制………………………………………7
4. MicroRNA與細胞先天免疫抗病毒反應…………………7
5. 病毒與microRNA的相互作用和影響……………………7
6. HCV與microRNA在複製、感染和致癌性的相關性………8
壹拾、 研究目標…………………9
壹拾壹、 材料與方法……10
1. 試劑…………10
2. 質體…………10
3. 細胞培養……10
4. 細胞轉染……11
5. 西方墨點法和蛋白質表現分析…………………11
6. RNA樣品製備與內生性microRNA表現量定量……11
7. 生物資訊工具 (Bioinformatics tools)………12
8. 統計分析……………………………………………12
壹拾貳、 結果
1. 細胞內有HCV Con1 full-genome replicon (FGR, Huh7.5-FGR)複製會影響內生性microRNA表現量……13
2. HCV結構性蛋白會調控HCV感染細胞的內生性microRNA的表現……………………………………13
3. HCVcore會調控Huh7.5-SGR的內生性microRNA表現量…14
壹拾參、 討論
1. 實驗結果的意義與討論……15
2. 實驗結果的延伸…16
3. Huh7.5-FGR vs Huh7.5-SGR與Huh7.5-SGR vs Huh7.5-SGR異位表達HCVcore對microRNA表現量的影響不一致…17
4. 與現有文獻的不同………18
5. 所選的microRNA與HCVcore在HCV之病理角色的關聯………19
壹拾肆、 參考文獻……20
壹拾伍、 表……35
壹拾陸、 圖……37
壹拾柒、 附錄…41
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