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系統識別號 U0026-2008201005454400
論文名稱(中文) ACSL3在肝細胞中的功能探討
論文名稱(英文) Study the Role of Acyl-CoA Synthetase Long-chain 3 in Liver Cells
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 98
學期 2
出版年 99
研究生(中文) 張永昇
研究生(英文) Yung-Sheng Chang
電子信箱 s5892110@mail.ncku.edu.tw
學號 s5892110
學位類別 博士
語文別 中文
論文頁數 98頁
口試委員 指導教授-賴明德
口試委員-戴明泓
口試委員-馬明琪
召集委員-呂增宏
口試委員-黎煥耀
口試委員-江美治
中文關鍵字 癌症  長鏈型醯基輔酵素A合成酵素  內質網壓力  脂質代謝異常  肝醣合成酶激酶-3  细胞週期蛋白  HBV突變型的大表面蛋白 
英文關鍵字 cancer  acyl-CoA synthetase long-chain  ER stress  lipid dysregulation  GSK-3  cyclin A  HBV 
學科別分類
中文摘要 內質網在細胞內參與了訊息傳遞與脂質生合成,因此內質網壓力產生時也會影響脂質的代謝。而在近來的研究中發現在肝癌細胞中,存在脂質代謝異常的現象,因此脂質代謝對於腫瘤細胞的生存與轉型具有相當重要的意義,而調控細胞脂質代謝也成為治療癌症的目標。本研究中使用多種訊息傳遞分子之抑制劑處理細胞,探討內質網壓力下調控細胞脂質代謝可能参與之分子與機轉。結果顯示長鏈型醯基輔酵素A合成酵素 (acyl-CoA synthetase long-chain, ACSLs) 的抑制劑Triacsin C,能有效的降低內質網壓力下脂質異常累積的現象。利用西方點墨法分析也可發現在HuH-7細胞或小鼠肝臟誘發內質網壓力的狀態下,ACSL3的表現量皆有顯著增加。以核醣核酸干擾技術 (RNAi) 抑制HuH-7細胞中的ACSL3,也可降低內質網壓力所導致的脂質累積現象。而ACSL3在內質網壓力下的表現量增加,則是透過GSK-3beta分子活化所造成。使用RNAi抑制HuH-7與HepG2細胞中GSK-3beta分子,也可降低內質網壓力造成的ACSL3表現。因此對於內質網壓力所造成的異常脂質累積上,ACSL3與GSK-3beta可作為治療上的新目標。
為了進一步探討ACSL3在肝癌致病機轉中所扮演的角色,將低表現ACSL3的細胞株以皮下注射方式至免疫缺失的小鼠 (NOD/SCID) 中,發現能顯著的降低腫瘤的生長能力,並延長小鼠的存活率。低表現ACSL3的細胞株或以ACSL3 shRNA轉染HEK293T的實驗中,發現只有細胞週期蛋白cyclin A的表現量顯著降低,且加入蛋白酶抑制劑則可回復cyclin A的表現。然而在其他低表現ACSLs的細胞株中,則無cyclin A表現量下降的現象。反之若在HuH-7與HEK293T細胞過度表現ACSL3分子,則能增加細胞內cyclin A的表現量。而當過度表現失去酵素活性的突變型ACSL3分子時,則無法增加細胞內cyclin A表現。在表現HBV突變型的大表面蛋白 (DelS2-LHBs) 的肝細胞中,也可觀察到脂質異常累積,cyclin A與ACSL3表現量增加的現象。當使用GSK-3beta抑制劑處理後可降低ACSL3表現,以Triacsin C或ACSL3 shRNA處理後可降低cyclin A的表現,而上述的處理皆可抑制DelS2-LHBs所造成的脂質累積。綜合上述的實驗結果,ACSL3對於腫瘤細胞的生長是必需,因此在未來可作提供作為癌症治療上的極佳標的。
英文摘要 Endoplasmic reticulum (ER) is an important organelle for lipid biosynthesis, and the ER stress signal is expected to cause alteration of lipid metabolism. Recent studies also indicated lipid metabolism was linked to cancer progression and downregulation of lipid metabolic genes was able to inhibit tumor formation. We first tested the effects of several inhibitors on the lipid dysregulation induced by ER stress inducer. Triacsin C, an inhibitor for long-chain acyl-CoA synthetases (ACSLs) was the most potent one among these inhibitors. We then determined the expression of ACSLs during ER stress. The expression of ACSL3 was induced by ER stress in HuH-7 cells and in mice liver. ACSL3 shRNA, but not ACSL1 shRNA, inhibited the induction of lipid accumulation during ER stress. GSK-3beta inhibitors attenuated ACSL3 expression and the lipid accumulation induced by ER stress in HuH-7 cells. Similarly, GSK-3beta shRNA also inhibited the upregulation of ACSL3 and lipid accumulation in HuH-7 and HepG2 cells. ACSL3 and GSK-3beta represent the novel therapeutic targets for lipid dysregulation by ER stress.
To further address that ACSL3 is important for the progression of hepatocarcinoma, HuH-7 cells and ACSL3 knockdown cells were subcutaneously injected into NOD/SCID mice. ACSL3 knockdown cells were grew much slower than HuH-7 cells in NOD/SCID mice. Examination of the expression of protein related with cell cycle or apoptosis revealed that only cyclin A was decreased. The cyclin A mRNA was unaltered by ACSL3 shRNA and the proteasome inhibitor restored the expression of cyclin A in HuH-7 cells or HEK293T cells. In contrast, ACSL1, 4, 5 shRNA did not affect cyclin A expression. On the other hand, overexpression of ACSL3 further enhanced cyclin A protein expression in HuH-7 cells or HEK293T cells. Mutant ACSL3 was unable to increase cyclin A protein level. Hepatitis B virus mutant large surface protein, which is known to induce ER stress, also increases ACSL3 expression, cyclin A expression, and lipid content. GSK-3beta inhibitors inhibited the expression of ACSL3 and the lipid dysregulation caused by hepatitis B virus mutant large surface protein. Addition of Triascin C or ACSL3 shRNA decreases the lipid content and cyclin A protein expression. In conclusion, ACSL3 is important for the growth of tumor cells and may represent a novel therapeutic target.
論文目次 I 緒論…………………………………………………………………………………1
I-1 脂質代謝異常和細胞週期調控在癌症中的關連性……………………………1
I-2 肝細胞內的脂肪合成途徑與調控因子…………………………………………3
I-3 醯基輔酵素A合成酵素的功能…………………………………………………5
I-4 醯基輔酵素A合成酵素與疾病或癌症的關連性………………………………6
I-5 內質網壓力的產生與脂質代謝的關連性………………………………………8
I-6 B型肝炎病毒大表面抗原突變株與癌症的關連性……………………………11
I-7 實驗目標與策略………………………………………………………………12
II材料與方法…………………………………………………………………………15
II-1 實驗藥物與試劑………………………………………………………………15
II-2 細胞培養………………………………………………………………………16
II-3 質體的構築……………………………………………………………………16
II-3-a構築shRNA質體……………………………………………………………16
II-3-b構築ACSL3與cyclin A的表現質體………………………………………17
II-4 穩定性轉染細胞株的建立……………………………………………………17
II-5 西方墨點法……………………………………………………………………18
II-6 反轉錄聚合酶連鎖反應………………………………………………………18
II-7 即時定量聚合酶連鎖反應……………………………………………………20
II-8 實驗動物與腫瘤植入…………………………………………………………20
II-9 油紅染色………………………………………………………………………20
II-10 誘導小鼠肝臟產生內質網壓力……………………………………………21
II-11 細胞週期分析………………………………………………………………21
II-12 統計分析……………………………………………………………………22
III 結果……………………………………………………………………………23
III-1 內質網壓力造成肝細胞內脂肪油滴累積…………………………………23
III-2 內質網壓力可調控ACSL家族的表現………………………………………24
III-3 小鼠動物模式中誘導內質網壓力也會造成脂質累積……………………25
III-4 抑制ACSL3可以減低內質網壓力造成的脂質累積情形…………………26
III-5 內質網壓力透過GSK-3beta來調控ACSL3表現…………………………28
III-6 內質網壓力下GSK-3beta與eIF-2alpha皆能調控NF-kappaB的活化……28
III-7 過度表現DelS2-LHBs能誘發內質網壓力並增加ACSL3的表現與脂質累積.30
III-8 ACSL3對於腫瘤的生長是必需的…………………………………………31
III-9 抑制ACSL3能降低cyclin A的蛋白質表現並改變細胞週期……………32
III-10 在293T細胞中抑制ACSL3也能降低cyclin A蛋白質表現……………33
III-11 過度表現ACSL3能增加cyclin A的蛋白質表現………………………34
III-12 ACSL3的酵素活性對於調控cyclin A的表現是必需的………………35
III-13 在DelS2-LHBs模式下抑制ACSL3也可降低cyclin A的過度表現……36
III-14 ACSL3 mRNA在臨床肝癌組織中有過度表現的情形……………………37
IV討論…………………………………………………………………………………39
IV-1 內質網壓力下ACSL3調控脂質代謝的重要性………………………………39
IV-2 內質網壓力下ACSL3的上游訊息傳遞路徑…………………………………41
IV-3 ACSL3調控cyclin A表現的可能機轉……………………………………42
IV-4 ACSLs在臨床肝癌組織中的表現……………………………………………44
V結論…………………………………………………………………………………46
VI參考資料……………………………………………………………………………47
VII附圖………………………………………………………………………………56
VIII自述……………………………………………………………………………97

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