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研究生:蒲芊彣
研究生(外文):Chien-Wen Pu
論文名稱:Statin Inhibits Large Hepatitis Delta Antigen-Smad3 -Twist-Mediated Epithelial-Mesenchymal Transition
論文名稱(外文):Statin抑制因大型D型肝炎抗原所誘導Smad3-Twist之表現與表皮-間質轉換
指導教授:吳肇卿
指導教授(外文):Jaw-Ching Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:70
中文關鍵詞:大型D型肝炎抗原表皮-間質轉換
外文關鍵詞:Large Hepatitis Delta AntigenEpithelial-Mesenchymal Transition
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猛爆性肝炎的重要原因之一為感染D型肝炎。此外在慢性B型肝炎患者中,重複感染 D型肝炎病毒則常會導致肝硬化或肝癌,目前尚無有效療法。D型肝炎病毒會編碼出小型和大型D型肝炎抗原 (S-HDAg and L-HDAg) ,小型D型肝炎抗原為HDV RNA複製所必須,而大型D型肝炎抗原須經異戊二烯化才能完成D型肝炎病毒之裝配。在我們先前研究說明,大型D型肝炎抗原可透過活化TGF-β來引起表皮-間質轉換,可能和肝纖維化與肝硬化相關,機制尚不清楚。本研究假設大型D型肝炎抗原可以活化表皮-間質轉換之主要調控者twist表現,誘導TGF-β與引起表皮-間質轉換,進一步導致肝纖維化。相反的,經statin類藥物處理來間接減少大型D型肝炎抗原的異戊二烯化,可能導致twist和TGF-β的表現降低並且影響表皮-間質轉換。本研究以人類肝癌細胞株HuH7,利用體外細胞培養模式轉染三種基因型之小型和大型D型肝炎抗原與空載體。以螢光素酶報導基因檢測、染色質免疫沉澱與免疫沉澱法,我們證實了大型D型肝炎抗原會透過與Smad3的相互作用專一性地活化twist的啟動子。更進一步,將twist 啟動子上的Smad結合位突變後,twist啟動子活性明顯被壓抑。利用酵素結合免疫吸附分析法測試,確認轉染大型D型肝炎抗原後,TGF-β分泌到細胞外的量有顯著升高。此外,表皮-間質轉換之特性與指標蛋白的表現也跟著增加。經六種statin分別以5μM與25μM處理高度表現小型或大型D型肝炎抗原之HuH7細胞。結果說明六種statin藥物皆因間接減少了大型D型肝炎抗原的異戊二烯化,而造成twist啟動子的活性下降。此外, Atrovastatin 和Simvastatin劑量與twist啟動子活性具有負相關。再者,經Simvastatin處理後,因大型D型肝炎抗原所造成的表皮-間質轉換之特性與指標蛋白的表現也隨之減少。總結之,大型D型肝炎抗原會與Smad3一起活化twist的表現,使得TGF-β表現量變高,而誘導表皮-間質轉換與其指標蛋白的表現。相反的,經由statin類藥物處理後,其特性皆降低。本研究結果顯示,statin類藥物除了降低膽固醇外,亦可能發展出治療慢性D型肝炎的新方法 。

HDV infection is one of the important causes of fulminant hepatitis. In addition, HDV superinfection in chronic hepatitis B patients may lead to cirrhosis or hepatocellular carcinoma (HCC). Currently, there is no effective treatment. HDV encodes small delta antigens (S-HDAg) and large form HDAg (L-HDAg). S-HDAg is essential for HDV RNA replication, while L-HDAg needs to be isoprenylated to perform HDV virions assembly. In our previous reports, L-HDAg transactivated TGF-β and induced epithelial-mesenchymal transition (EMT) which may contribute to liver fibrosis. However, the mechanism is unclear. In this study, we hypothesized that L-HDAg can activate twist, the major regulator of EMT, expression which induces TGF-β, EMT, and may further lead to liver fibrosis. On the contrary, statin treatment may indirectly decrease isoprenylation of L-HDAg. As a result, expression of twist and TGF-β may be down-regulated, which may lead to the decrease of EMT. In this study, human HCC cell line HuH7 was transfected in vitro with three genotypes of S-HDAg, L-HDAg and vector. Using luciferase reporter, chromatin immunoprecipitation and co-immunoprecipitation assays, we confirmed that L-HDAg specifically activated twist promoter through interaction with Smad3. Furthermore, mutation of Smad-binding element in twist promoter significantly repressed twist promoter expression. Six types of statin were used in the treatment of HuH7 cells which transfected with L-HDAg or S-HDAg at a concentration of 5μM and 25μM. The result showed that all six statins indirectly decrease isoprenylation of L-HDAg and further reduced twist expression. In addition, we also observed that a dose-dependent negative correlation between Atrovastatin/ Simvastatin treatment and twist promoter activity. Furthermore, statin treatment lead to the reduction of EMT and EMT markers expression. In conclusion, L-HDAg interacted with Smad3 and activated twist promoter. Activated twist promoter increased the expression of TGF-β, which lead to the induction of EMT and EMT markers expression. On the contrary, TGF-β expression and the properties of EMT are decreased after statin treatment. This study demonstrated that in addition to decrease cholesterol biosynthesis, statin also showed great potential as a novel therapy for the treatment of chronic hepatitis D.

Contents ........................................................I
Abstract................................................II
中文摘要.................................................III
List of Abbreviations...................................IV
Introduction ........................................... 1
I. Epidemiology of Hepatitis D virus (HDV).............. 2
II. Structure of HDV and HDV RNA ....................... 3
III. Hepatitis Delta Antigen (HDAg) Structure and function ........................................................ 4
IV. The Treatment and Prevention of HDV..................................................... 5
V. Transforming Growth Factor β (TGF -β)................ 7
VI. Epithelial mesenchymal transition (EMT)............. 7
VII. Statin............................................. 9
Rational, Hypothesis and Aims .......................... 10
Experimental designs.....................................12
Materials and Methods................................... 13
Results................................................. 26
Discussion...............................................34
References...............................................40
Figures................................................. 52
Figure 1. L-HDAg specifically activated the twist promoter. ........................................................ 53
Figure 2. HDAg bound to the SBE of twist promoter. ........................................................ 54
Figure 3. HDAg specifically interacted with Smad3 protein bound to the SBE in the twist proximal promoter......... 55
Figure 4. Comparison of fold-changes in luciferase activity of pXP2-Twist or pXP2-Twist-mutant promoter activated by L-HDAg, L-C211S mutant or S-HDAg in HuH7 cells............ 56
Figure 5. The expressed protein levels of Smad3 in HuH7 cells after knockdown of Smad3...........................57
Figure 6. L-HDAg activated the twist promoter through interacting with Smad3...................................58
Figure 7. L-HDAg C211S mutants of three genotypes could not activate twist promoter activity.........................59
Figure 8. Atorvastatin suppressed the twist promoter activity through indirectly decrease isoprenylation of L-HDAg........ ........................................... 61
Figure 9. Fluvastatin suppressed the twist promoter activity through indirectly decrease isoprenylation of L-HDAg......... .......................................... 63
Figure 10. Lovastatin repressed the twist promoter activity through indirectly decrease isoprenylation of L-HDAg.................................................... 64
Figure 11. Pravastatin suppressed through indirectly decrease isoprenylation of L-HDAg....................... 65
Figure 12. Rosuvastatin repressed the twist promoter activity through indirectly decrease isoprenylation of L-HDAg................................................... 66
Figure 13. Simvastatin suppressed the twist promoter activity through indirectly decrease isoprenylation of L-HDAg................................................... 67
Figure 14. Simvastatin effectively reduced TGF-β secretion in HuH7 cells.......................................... 68
Figure 15. Expression levels of EMT markers and regulators after simvastatin treatment in L-HDAg-expressing HuH7 cells.................................................. 69
Figure 16. Summary schema...............................70
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