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    題名: 含EBV病毒產物之外吐小體對鼻咽癌細胞及微環境基質細胞的調控;Ebv Products-Containing Exosome-Mediated Intercellular Regulation between Npc Cells and Niche Stromal Cells
    作者: 劉淑貞;曾雁明
    貢獻者: 國立中央大學生醫科學與工程學系
    關鍵詞: 鼻咽癌;外吐小體;成纖維母細胞;腫瘤基質;EB病毒;EBV潛伏膜蛋白-1;nasopharyngeal carcinoma;exosome;fibroblasts;tumor stroma;Epstein-Barr virus;LMP1
    日期: 2018-12-19
    上傳時間: 2018-12-20 11:29:29 (UTC+8)
    出版者: 科技部
    摘要: WHO type III 鼻咽癌(NPC)幾乎皆具有EB病毒(EBV)感染及腫瘤組織發炎免疫細胞浸潤的特徵。近年研究顯示腫瘤微環境中含有大量的外吐小體(exosomes),外吐小體在細胞間傳遞生物活性物質,造成免疫細胞活化或抑制,血管新生,及促進癌轉移而影響癌症的惡性化程度。研究證據顯示有EB病毒感染的鼻咽癌細胞可藉由釋出的外吐小體傳遞EB病毒產物至未被病毒感染的癌細胞或免疫細胞。然而,含EB病毒產物的外吐小體如何調控微環境中的細胞仍待進一步研究。在腫瘤微環境中,成纖維母細胞(fibroblasts)是腫瘤基質中的主要細胞類型。我們初步研究結果顯示,成纖維母細胞攝入含有EB病毒潛伏膜蛋白-LMP1的外吐小體後會誘導成纖維母細胞分化成類肌纖維母細胞(myofibroblast-like) 形態(即活化的成纖維母細胞),此結果可由增強的 alpha-SMA蛋白表現和張力絲(stress fiber)型態的改變證實。若成纖維母細胞表現EBV-LMP1蛋白則會活化多個訊息傳導路徑中的激酶,包含NF-kB, JNK, MAPK, ERK1/2 及AKT。此外,成纖維母細胞的活化可能受nuclear YAP1調控。免疫組織染色結果顯示鼻咽癌腫瘤基質中的nuclear YAP1的表現量與有EBV感染腫瘤周圍區域的纖維化反應相關。綜合初步實驗結果,EBV或EBV產物相關的外泌小體可能調控腫瘤基質環境而使腫瘤細胞和病毒本身受益。於此研究計畫中,我們將研究含有EB病毒產物的外吐小體對鼻咽癌基質細胞的影響。主要研究目標包括:(1)評估鼻咽癌微環境中含有EBV產物的外吐小體是否調控與重塑鼻咽癌基質結構,構成促進腫瘤生長的微環境; (2)透過RNA定序與蛋白質體實驗對鼻咽癌細胞所釋出的外吐小體及鼻咽癌病人血液中的外吐小體做全面性的分析以瞭解其中所含生物活性物質及其生物效應; 3)評估應用外吐小體做為穩定液體標幟分子,用於鼻咽癌診斷和預後的可行性; 4)研究針對特定外吐小體表面蛋白來抑制腫瘤生長的可能性,期望藉由阻礙外吐小體生物物質的傳遞破壞有利腫瘤生長的微環境。 ;The WHO type III nasopharyngeal carcinoma is characterized by Epstein-Barr virus (EBV) infection and intensive immune cell infiltration within tumors. Emerging evidences suggest that exosomes presented in the tumor microenvironment modulate tumor progression by regulating immunity, angiogenesis, and metastasis. Recent studies reveal that EBV positive cancer cells can horizontally transfer EBV-encoded products, such as miRNAs, LMP1, to EBV-negative cancer cells as well as immune cells through exosome cargo. However, the functional consequence induced by the EBV-associated exosomes remains to be determined. In tumor microenvironment, fibroblasts are recognized as the primary cell type in tumor stroma. Our preliminary data showed that treating primary fibroblasts with EBV-LMP1-containing exosomes induced a myofibroblast-like morphology (activated fibroblasts) as supported by the enhanced alpha-SMA expression and extensive formation of stress fiber. Further, we found that expression of LMP1 in human primary fibroblasts could activate multiple signaling molecules, including NF-kB, JNK, MAPK, ERK1/2 and AKT. We further found that the activation of fibroblasts might be regulated by YAP/TAZ. Immunohistochemical data demonstrated a strong nuclear YAP1 expression in cancer-associated fibroblasts, and that correlated with fibrotic response in the vicinity of EBERs-positive NPC tumors. So far, our data suggested that EBV and/or EBV products-associated exosomes could modulate tumor stroma. In this project, we will continue to investigate how EBV and EBV-encoded products remodel the NPC tumor stroma and whether this modulated tumor niche benefits tumor cells and virus itself. Primary goals of this project comprise: (1) evaluating whether EBV products-containing exosomes remodel NPC stromal structure to constitute a tumor-promoting microenvironment; (2) comprehensive profiling of exosomes derived from EBV+-NPC cells and plasma samples of NPC patients by utilizing RNA sequencing and proteomic studies; (3) assessing the potentiality of using exosome-based liquid biopsies for diagnosis and prognosis; (4) investigating the possibility of recessing tumor growth by targeting to specific exosomal molecules in a hope to develop therapeutic strategy by breaking down the infrastructure of tumor. Given the role of tumor stroma in cancer progression, it could be a promising strategy to target the environmental EBV-related products to regress disease.
    關聯: 財團法人國家實驗研究院科技政策研究與資訊中心
    顯示於類別:[生醫科學與工程學系] 研究計畫

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