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研究生:饒芸嘉
研究生(外文):Yun-Chia Jao
論文名稱:Mir-320藉由減少Neuropilin1的表現來調控血管內皮細胞的功能
論文名稱(外文):Mir-320 regulates vascular endothelial cell function by decreasing expression of Neuropilin 1
指導教授:陳玉玲陳玉玲引用關係
指導教授(外文):Yuh-Ling Chen
學位類別:碩士
校院名稱:國立成功大學
系所名稱:口腔醫學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:83
中文關鍵詞:血管新生內皮細胞缺氧miR-320neuropilin 1
外文關鍵詞:neuropilin 1miR-320angiogenesishypoxiaendothelial cell
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MicroRNA (miRNA)是內源性非編碼的單股小RNA,藉由與mRNA結合來抑制其mRNA的轉譯或使其降解而負調控基因的表現。近年研究顯示miRNA在多種腫瘤與正常組織間表現量不同且與癌症形成有關。miRNA藉由改變與腫瘤形成相關基因的表現量而作為腫瘤抑制基因或是致癌基因。實驗室先前藉由微陣列方式發現miR-320在口腔癌細胞株(OC2)的表現量比在正常人類口腔角質細胞中表現量低。在分析臨床口腔癌病人的腫瘤組織與非腫瘤組織的配對檢體中也發現,mir-320在腫瘤組織中的表現量比在非腫瘤組織中明顯減少。藉由軟體分析,結果預測neuropilin 1 (NRP1)可能為miR-320調控的標的基因。NRP1在神經及血管發展扮演重要角色,它可作為一受體與軸突導向分子semaphorine家族或血管新生刺激因子VEGF家族結合。在許多文獻指出NRP1會促進腫瘤血管新生、血管內皮細胞的移行以及腫瘤轉移。在此研究我們進一步分析miR-320是否會調控NRP1在後轉錄階段的表現,結果發現將miR-320的前驅分子或抑制劑送入人類臍帶血管內皮細胞(HUVECs) 中皆能影響NRP1的表現,利用報導基因表現分析也證實miR-320確實可透過結合在NRP1的3’UTR上而影響冷光表現。我們發現miR-320可藉由減少NRP1表現而抑制血管內皮細胞的移行及貼附。此外,我們發現血管內皮細胞在缺氧以及養分缺乏下miR-320表現量會下降且NRP1表現量會上升。利用in situ hybridization及免疫組織化學染色分析臨床檢體發現在OSCC組織中的血管其miR-320表現下降並與NRP1表現具有相關性。綜合以上結果顯示,miR-320在腫瘤組織中的血管內皮細胞表現量減少可能參與調節腫瘤血管新生的功能。
MicroRNAs (miRNAs) are endogenous small noncoding RNAs that reduce the translation of mRNAs or cause mRNA degradation by targeting mRNAs. Recent evidences have shown that a number of miRNAs are differentially expressed in various tumors vs. normal tissues and associated with cancer development. MiRNAs change in the amounts of these RNAs can be tumorigenic or tumor suppressive if they target mRNAs for either a tumor suppressor or an oncogene. In the previous study, we found that the expression of miR-320 was lower in oral cancer cells (OC2) than in normal human oral keratinocytes by microarray analyses. In the analysis of clinical OSCC match-pair tissues, we also found that miR-320 were significantly down-regulated in oral cancer specimens. By using the bioinformatic tools at the miRNA target database, neuropilin 1 (NRP1) was predicted to be a target of miR-320. NRP1 plays a central role in neuronal and blood vessel development as a receptor for two ligand types, the semaphorin family of axon guidance modulators and the VEGF family of angiogenesis stimulators. Several studies showed that NRP1 promoted tumor angiogenesis, vascular endothelial cells migration, and tumor metastasis. In this study, we found that miR-320 regulates the expression of NRP1 at a posttranscriptional level by transfecting miR-320 precursor or antagomiR-320 in human umbilical vein endothelial cells (HUVECs). Using luciferase reporter assays we confirmed that miR-320 could reduce luciferase expression by binding 3’ UTR of NRP1. MiR-320 reduced HUVECs migration and adhesion by decreasing expression of NRP1. Furthermore, we found that hypoxia-nutrients deprivation reduced expression of miR-320 and increase NRP1 level in HUVECs. Clinical specimens’ examination by in situ hybridization and immunohistochemistry analyses also showed that miR-320 expression was down-regulated and inversely correlated with NRP1 expression status in the blood vessels of OSCC tissues. Taken together, our present study revealed that miR-320 was down-regulated in cancer-associated vascular endothelial cells and might modulate tumor angiogenesis.
目錄
中文摘要 I
英文摘要 II
致謝 IV
目錄 V
表目錄 VIII
圖目錄 IX
附錄目錄 X
英文縮寫檢索表 XI
緒論 1
MicroRNAs 1
MicroRNA的生成與生物功能 1
血管新生的過程及調控 3
缺氧(hypoxia)/局部缺血(ischemia)調控血管新生 5
Neuropilin 1 7
研究動機 10
材料與方法 11
一、細胞培養 11
1-1 人類臍帶靜脈內皮細胞 11
1-2 繼代培養 12
1-3 冷凍保存細胞 12
1-4細胞解凍 13
1-5 細胞計數 13
二、細胞內RNA表現分析 14
2-1 RNA萃取 14
2-2 RNA及DNA的定量 14
2-3 反轉錄酶反應(reverse transcription) 15
2-4 聚合酶連鎖反應(polymerase chain reaction, PCR) 16
2-5 洋菜膠體電泳分析(agarose gel electrophoresis) 17
2-6 MicroRNA即時定量PCR (qRT-PCR) 18
三、細胞蛋白質表現分析 20
3-1 細胞蛋白質收集 20
3-2 西方墨點法(Western blot assay) 21
四、NRP1 3’UTR之報導基因載體構築 24
五、轉型作用(transformation) 26
六、NRP1 3’UTR之報導基因表現分析(reporter assay) 26
6-1 microRNA與報導基因載體之轉染(transfection) 26
6-2 Luciferase與β-galactosidase之訊號偵測 27
七、MiR-320對血管內皮細胞功能影響之實驗 28
7-1 MicroRNA之細胞轉染 28
7-2 細胞移行分析 29
7-3 細胞增生分析 29
7-4 細胞貼附實驗 30
八、細胞缺氧及營養缺乏實驗 30
九、檢體組織之冷凍切片準備 31
9-1 檢體組織之準備 31
9-2 冷凍切片 32
十、冷凍切片之microRNA in situ hybridization 32
十一、冷凍切片之免疫組織化學染色(immunohistochemistry) 34
十二、統計分析 36
實驗結果 37
一、miR-320可能調控的目標基因 37
二、miR-320會影響血管內皮細胞HUVECs的NRP1表現 37
三、miR-320會藉由直接結合在NRP1 mRNA 3’UTR上進而調控NRP1的表現 38
四、HUVECs內生性的miR-320會結合在NRP1 mRNA 3’UTR上進而調控NRP1的表現 39
五、miR-320會抑制血管內皮細胞HUVECs的移行但不會影響生長能力 40
六、miR-320會抑制血管內皮細胞HUVECs的貼附能力 41
七、在缺氧及營養缺乏情況下會抑制血管內皮細胞HUVECs的miR-320表現 41
八、miR-320抑制VE-cadherin的表現可能是透過抑制NRP1表現所造成 42
九、臨床OSCC組織中的血管其miR-320表現下降並與NRP1表現具有負相關性 43
討論 45
結論 52
參考資料 53
自述 83
表目錄
表一、miR-320表現與35組OSCC臨床病理多因素之關係。 62
圖目錄
圖一、miR-320在35組OSCC檢體中的表現。 63
圖二、miR-320在各種不同細胞間的表現。 64
圖三、NRP1 mRNA 3’UTR上的兩個miR-320可能的結合位。 65
圖四、NRP1表現量會受到miR-320 precursor轉染至HUVECs中而減少。 66
圖五、NRP1表現量會受到antagomiR-320轉染至HUVECs中而增加。 67
圖六、NRP1 3’UTR reporter之建構。 68
圖七、miR-320會直接結合在NRP1 mRNA 3’UTR上。 69
圖八、內生性miR-320會直接結合在NRP1 mRNA 3’UTR上。 70
圖九、利用PicTar線上miRNA 資料庫來分析miR-320可能調控的基因。 71
圖十、內生性miR-320對NRP1 3’UTR reporter activity的影響。 72
圖十一、miR-320會抑制血管內皮細胞HUVECs的移行。 73
圖十二、miR-320不會影響血管內皮細胞HUVECs的生長。 74
圖十三、miR-320會抑制血管內皮細胞HUVECs的貼附。 75
圖十四、在缺氧及營養缺乏情況下會使血管內皮細胞HUVECs的miR-320表現量減少,NRP1表現量增加。 76
圖十五、HUVECs在不同變因數組合下其miR-320的表現。 77
圖十六、miR-320會抑制VE-cadherin的表現可能是透過抑制NRP1表現所造成。 78
圖十七、分析臨床OSCC組織中的血管其miR-320以及NRP1的表現。 79
圖十八、分析臨床OSCC組織中的血管其miR-320與NRP1的表現及其相關性。 80
附錄目錄
附錄一:抗體 81
附錄二、儀器 82
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