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研究生:林怡亭
研究生(外文):Lin, Yi-Ting.
論文名稱:蟲草素透過調節FAK和p53抑制內皮細胞增生、轉移、血管新生及腫瘤生長
論文名稱(外文):Cordycepin suppresses endothelial cell proliferation, migration, angiogenesis and tumor growth by regulating focal adhesion kinase and p53
指導教授:劉俊揚劉俊揚引用關係莊永仁
指導教授(外文):Liou, Jun-YangChuang, Yung-Jen
口試委員:汪宏達林秀芳郭呈欽
口試委員(外文):Wang, Horng-DarYet, Shaw FangKuo, Cheng-Chin
口試日期:2020-01-22
學位類別:博士
校院名稱:國立清華大學
系所名稱:生物資訊與結構生物研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:67
中文關鍵詞:血管新生蟲草素內皮細胞黏著斑激酶p53腫瘤抑制蛋白
外文關鍵詞:angiogenesiscordycepinendothelial cellsFAKp53
相關次數:
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蟲草素亦稱為3'-脫氧腺苷,為腺苷之類似物。蟲草素為冬蟲夏草中主要的活性化合物,已被發現其具有增強免疫力、抑制腫瘤生長及血管新生等功用。在我們先前的研究中表明,蟲草素透過調控整聯蛋白及黏著斑激酶 (integrin/FAK) 之訊息傳遞路徑降低肝癌細胞之上皮-間質轉化 (EMT) 。黏著斑激酶 (FAK) 為一種調節血管發育之細胞基質激酶,其在細胞中扮演著重要的角色,包括調節內皮細胞 (EC) 之貼附、遷移、增生及存活等。然而,蟲草素對於內皮細胞之血管新生作用仍是未知的。於本研究中,我們發現蟲草素抑制內皮細胞中黏著斑激酶之活性及Y397位點之磷酸化,進而降低細胞遷移及增生。於共聚焦顯微鏡檢查中顯示,蟲草素顯著的減少黏著斑激酶之表現及數量。此外,蟲草素亦增加了p53及p21蛋白質之表達,從而導致G1細胞週期停滯。最後,在體外及體內模型中皆顯示出蟲草素抑制血管新生。我們透過體外血管新生分析發現處理蟲草素的實驗組抑制了體外血管管腔之生成,另一方面在實驗鼠中亦發現蟲草素抑制了血管新生。綜合以上結果表明,蟲草素可能透過抑制黏著斑激酶之表達及增加p53和p21蛋白質表現量來抑制內皮細胞中之血管生成、細胞遷移和增殖。我們的結果顯示,蟲草素可能具有用於預防血管新生的潛在治療或輔助化合物之潛力。
Cordycepin, known as 3’-deoxyadenosine, is an analogue of adenosine. Cordycepin is the major active compound in Dong Chong Xia Cao which has been found to enhance immune function and inhibit tumor growth and angiogenesis formation. Our previous study indicated that cordycepin reduced the epithelial-mesenchymal transition (EMT) via the integrin/FAK signaling in hepatocellular carcinoma. Focal adhesion kinase (FAK) is a cytoplasmic kinase that regulates vascular development, including the endothelial cell (EC) adhesion, migration, proliferation, and survival. However, the effect of cordycepin on angiogenesis formation is still underdetermined. In this study, we found that cordycepin inhibits activation of FAK and phosphorylates FAK at the position of Y397 in ECs leading to suppression of cell migration and proliferation. Confocal microscopy indicated that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. In addition, cordycepin increased the protein expression of p53 and p21 which causes the G1 cell-cycle arrest. Finally, the treatment of cordycepin inhibited the tube formation and angiogenesis in the in vitro and in vivo model. These results suggest that cordycepin may inhibit angiogenesis, cell migration and proliferation in ECs via suppressing FAK expression and increasing p53 and p21 expression. As a result, cordycepin may be a potential therapeutic or supplementary compound used for preventing angiogenesis.
DISCLOURS AND PUBLIACTION LIST i
ABSTRACT ii
中文摘要 iv
致謝 v
LIST OF CONTENTS vi
LIST OF TABLES ix
LIST OF FIGURES x
ABBREVIATION xi
CHAPTER I: General introduction and literature review 1
Focal adhesion kinase (FAK) 2
The interaction of FAK and p53 regulates cell survival and cell cycle in tumorigenesis 4
The role of FAK signaling pathway in promoting tumor progression and metastasis 5
The role of angiogenesis in HCC 7
Cordycepin 9
CHAPTER II: Materials and Methods 12
Cell culture and reagents 13
Western blot analysis 13
Quantitative real-time PCR (qPCR) 14
Cell migration and wound healing analysis 15
Cell proliferation analysis 16
Flow cytometry analysis 16
Tube formation 17
Immunofluorescence confocal microscopy 17
In vivo matrigel plug angiogenesis assay 18
Tumor xenograft experiments 19
Statistical analysis 19
Tables 20
CHAPTER III: Results 23
Cordycepin reduces FAK expression and phosphorylation in ECs 24
Cordycepin suppresses cell migration and proliferation 25
Cordycepin inhibits tube formation and in vivo angiogenesis 27
Cordycepin reduces the cytoplasmic expression of cytosolic FAK in HUVECs 28
Cordycepin up-regulates p53 and p21 expression levels in ECs 29
Cordycepin inhibits FAK/p-FAK expression and cell proliferation on HCC 30
Cordycepin suppresses in vivo tumor growth of HCC in BALB/c mice 30
CHAPTER IV: Discussion and conclusion 50
Discussion 51
Conclusion 56
References 59
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