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研究生:高亦欣
研究生(外文):Yi-Hsin Kao
論文名稱:探討PODXL基因在神經母細胞瘤扮演之角色
論文名稱(外文):Investigating the role of PODXL in neuroblastoma
指導教授:胡忠怡
口試委員:周獻堂林亮音歐大諒
口試日期:2019-07-23
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:138
中文關鍵詞:神經母細胞瘤PODXL微核醣核酸-125b慢病毒載體癌症表現型
DOI:10.6342/NTU201903518
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  神經母細胞瘤(Neuroblastoma, NB)為兒童最常見之顱外固態腫瘤(extracranial solid tumor)。其成因被認為主要由於神經嵴前驅細胞(neural crest progenitors)分化失敗並異常增生所導致。然而此疾病異質性極高,致病機制也尚未明瞭,故高風險神經母細胞瘤患者即使經強力治療後,其長期存活率仍低於四成。目前MYCN基因擴增為神經母細胞瘤最重要的不良預後因子,因此科學家在尋找高風險神經母細胞瘤之治療標的時,對MYCN基因上下游調控網路特別感興趣。
  由本實驗室有關神經母細胞瘤與微核醣核酸(microRNA, miRNA)之系列研究發現神經母細胞瘤腫瘤中若表現較高的miR-125b,則病患之長期存活率顯著較好。於MYCN擴增之神經母細胞瘤細胞株過表現miR-125b會導致細胞分化、細胞週期停滯、降低細胞遷移與侵襲能力,顯示miR-125b於此疾病扮演抑癌之角色。我們由微陣列(microarray)分析有無過表現miR-125b神經母細胞瘤細胞之差異表現基因,其中包括LIN28B和PODXL。
  Podocalyxin-Like Protein 1(PODXL)屬於CD34家族成員,是細胞表面高度糖化的穿膜蛋白。過往文獻提及,PODXL於多種癌症中有過表現的情況,並與較具侵襲性之腫瘤以及預後不良相關;亦有研究指出PODXL之高表現與癌細胞之遷移、侵襲、上皮-間質轉換(epithelial-mesenchymal transition, EMT)和轉移有關。在閉塞性動脈硬化(atherosclerosis obliterans)相關研究中亦已證實miR-125b可直接負調控PODXL表現並影響人類主動脈血管平滑肌細胞(human aortic vascular smooth muscle cells, HAVSMCs)之增生與移動,本研究的目的為於神經母細胞瘤中確認miR-125b/PODXL調控路徑之存在,並探討PODXL在神經母細胞瘤腫瘤生成與發展中扮演之角色。
  我們在神經母細胞瘤SK-N-DZ細胞株中過表現miR-125b,會導致其PODXL表現減弱,顯示神經母細胞瘤系統中PODXL基因受miR-125b之負向調控。且於四十位神經母細胞瘤病人臨床檢體中,miR-125b與PODXL基因表現量呈負相關。此外,以公開的R2資料庫內三個神經母細胞瘤資料集(Versteeg-88, NRC-283, TARGET-249)進行分析,發現PODXL高表現之病患存活率顯著較差;且高風險分期病患之PODXL表現顯著高於低風險分期者。接著我們利用慢病毒(lentivirus)將shPODXL送入SK-N-DZ細胞干擾PODXL表現,藉此探究PODXL對於癌症表現型的影響。抑制PODXL的SK-N-DZ細胞,其遷移、侵襲,與非貼附生長能力皆顯著降低;而其增生則不受影響。有趣的是,我們發現抑制PODXL能使間質細胞表型的標記-vimentin以及N-cadherin蛋白質表現降低,暗示著PODXL的表現可能參與調節細胞的EMT。
  綜合本研究所得之結果推論PODXL可能會透過促進腫瘤細胞遷移與侵襲,而對神經母細胞瘤之腫瘤侵襲性(tumor aggressiveness)有所貢獻。且於神經母細胞瘤中,PODXL的表現受miR-125b負向調控。此外,PODXL高表現之神經母細胞瘤病患預後較差。因此在未來,原發腫瘤中PODXL之表現可望成為惡性神經母細胞瘤重要的分子標記之一,探討PODXL相關網路的調控有助於研發高風險性神經母細胞瘤之治療標的。
  Neuroblastoma (NB) is the most common extracranial solid tumor in pediatric malignancies. It is thought to be derived from the failure of differentiation and abnormal proliferation of neural crest progenitors. Neuroblastoma is characterized by the heterogeneity in clinical behavior and unclear pathogenesis. The long-term survival of high-risk neuroblastoma is still under 40 percent after intensive therapy. MYCN amplification is the most important inferior prognostic factor of NB. Regulatory networks upstream or downstream of MYCN are of particular interest in searching for the therapeutic target in high-risk neuroblastoma.
  We previously found that higher miR-125b expression level in the tumor was associated with better long-term survival in neuroblastoma. Overexpression of miR-125b in MYCN-amplified NB cells led to cell differentiation, cell cycle arrest, reduced cell growth, anchorage-independent cell growth, cell migration and invasion suggested miR-125b plays as a tumor suppressor in neuroblastoma. Microarray analysis of miR-125b-overexpressed versus control NB cells revealed several candidate targets, including LIN28B and PODXL.
  Podocalyxin-like protein 1 (PODXL), is a transmembrane glycoprotein of the CD34 family. PODXL was found being overexpressed in several kinds of carcinoma and was associated with more aggressive tumors and poorer prognosis. High PODXL expression was related to tumor migration, invasion, epithelial-mesenchymal transition (EMT), and metastasis. PODXL was shown to be a direct target of miR-125b that mediate the proliferation and migration of human aortic vascular smooth muscle cells (HAVSMCs). In this study, we aim to confirm the miR-125b/PODXL regulatory pathway and to investigate the role of PODXL in neuroblastoma tumorigenesis and development.
  Expression of PODXL was suppressed in response to miR-125b overexpression in SK-N-DZ NB cells, indicated that PODXL was negatively regulated by miR-125b in neuroblastoma. Also, in a cohort of 40 NB patients, the expression of PODXL and miR-125b in tumor samples showed a negative correlation. In addition, by analyzing three neuroblastoma datasets(Versteeg-88, NRC-283, TARGET-249)in the public R2 database, it was found that high PODXL expression was significantly correlated with the poor survival of patients. PODXL expression is higher in the tumor of advanced stages. We used lentivirus to deliver shPODXL into SK-N-DZ cells to elucidate the role of PODXL plays in oncogenic phenotypes. In PODXL repressed SK-N-DZ cells, the capabilities of migration, invasion, and anchorage-independent cell growth were significantly reduced while the proliferative expansion of the cells was not affected. Interestingly, expression of vimentin and N-cadherin were downregulated in response to PODXL repression, suggesting PODXL may participate in the regulation of EMT.
  In summary, PODXL may promote tumor migration and invasion, thus contributes to tumor aggressiveness in neuroblastoma, while its expression was negatively regulated by miR-125b. High level of PODXL was associated with poor prognosis in neuroblastoma. PODXL expression in the primary tumor might serve as a molecular marker in advanced NB. In depth research of the regulatory network implicated in PODXL-mediated aggressive phenotypes may help to define potential therapeutic targets for advanced neuroblastoma.
致謝 I
摘要 II
Abstract IV
縮寫表 VI
目錄 XI
圖目錄 XV
表目錄 XVII
附錄目錄 XVIII
第一章 緒論 1
1.1 神經母細胞瘤 1
1.1.1 神經母細胞瘤簡介 1
1.1.2 神經母細胞瘤之致病機轉 1
1.1.3 神經母細胞瘤之臨床表現 2
1.1.4 神經母細胞瘤之病理特徵與分類 3
1.1.5 神經母細胞瘤之疾病診斷與分期 4
1.1.6 神經母細胞瘤之分子標記及預後指標 5
1.1.7 神經母細胞瘤之治療策略 8
1.2 PODXL基因 10
1.2.1 PODXL基因簡介 10
1.2.2 PODXL基因與癌症 12
1.2.3 PODXL基因與微核醣核酸 14
1.3 微核醣核酸 15
1.3.1  微核醣核酸簡介 15
1.3.2 微核醣核酸之生理功能與意義 16
1.3.3 微核醣核酸與癌症 17
1.3.4 微核醣核酸-125b簡介 18
1.3.5 微核醣核酸-125b與癌症 19
1.3.6 微核醣核酸-125b在神經母細胞瘤中之抑癌作用 21
1.4 研究動機與假說 22
第二章 研究目的與實驗設計 23
2.1 研究目的 23
2.2 實驗設計 23
第三章 材料與方法 25
3.1 實驗材料 25
3.1.1 R2資料庫 25
3.1.2 細胞株 25
3.1.3 臨床檢體 26
3.1.4 試藥、試劑清單 26
3.1.5 試劑套組 29
3.1.6 抗體清單 30
3.1.7 溶液試劑配方 30
3.1.8 實驗儀器 37
3.1.9 質體 38
3.1.10 引子序列 38
3.1.11 軟體與網路工具 39
3.2 實驗方法 40
3.2.1 解凍細胞、繼代培養、凍存細胞 40
3.2.2 慢病毒製備 41
3.2.3 慢病毒濃縮 41
3.2.4 測試病毒力價(titer) 42
3.2.5 慢病毒轉導(lentiviral transduction) 43
3.2.6 酸性磷酸酶試驗(Acid phosphatase assay, ACP assay) 43
3.2.7 細胞生長與活性分析 43
3.2.8 遷移能力試驗(Migration assay) 44
3.2.9 侵襲能力試驗(Invasion assay) 44
3.2.10 非貼附生長能力試驗(anchorage-independent growth ability assay) 45
3.2.11 核醣核酸萃取(Total RNA extraction) 46
3.2.12 核醣核酸相對表現量(RNA relative expression) 46
3.2.13 微核醣核酸相對表現量(miRNA relative expression) 49
3.2.14 西方墨點法(Western blot) 50
3.2.15 數據統計及分析 53
第四章 結果 54
4.1 PODXL基因與miR-125b表現量於神經母細胞瘤中呈現負相關 54
4.1.1 台大醫院臨床檢體 54
4.1.2 神經母細胞瘤細胞株 54
4.2 分析PODXL基因表現量與病患存活率及臨床特徵之相關性 55
4.2.1 R2資料庫-Versteeg-88 dataset 55
4.2.2 R2資料庫-NRC-283 dataset 56
4.2.3 R2資料庫-TARGET-249 dataset 56
4.2.4 台大醫院神經母細胞瘤臨床檢體 57
4.3 在神經母細胞瘤細胞株抑制PODXL基因表現對細胞表型之影響 59
4.3.1 神經母細胞瘤細胞株之PODXL基因表現量 59
4.3.2 利用shRNA抑制神經母細胞瘤細胞株之PODXL基因表現 59
4.3.3 抑制PODXL基因表現不影響神經母細胞瘤細胞株之生長與存活率 59
4.3.4 抑制PODXL基因表現能減緩神經母細胞瘤細胞株之惡性度 60
4.3.5 抑制PODXL基因表現對神經母細胞瘤細胞株EMT之影響 62
第五章 討論 63
參考文獻 68
圖 91
表 115
附錄 117
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