請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71235
標題: | 黏蛋白第二十型在胰臟癌中扮演的角色 The role of MUC20 in pancreatic cancer |
作者: | Syue-Ting Chen 陳學亭 |
指導教授: | 黃敏銓(Min-Chuan Huang) |
共同指導教授: | 田郁文(Yu-Wen Tien) |
關鍵字: | 胰腺癌,胰臟星狀細胞,黏液蛋白第二十型 (MUC20), Pancreatic ductal adenocarcinoma (PDAC),Pancreatic stellate cell (PSC),MUC20, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 胰臟癌在十大癌症死因中排名第四位,大部份為胰腺癌。胰腺癌通常由胞外基質及星狀細胞共同形成的緻密纖維化基質所包覆,而由此纖維化基質所營造出的低養分,低氧及酸性的微環境促進了胰腺癌細胞的惡性行為。黏液蛋白(Mucins)為高度醣化之蛋白質,在惡性腫瘤的發病機轉中扮演重要角色。據研究顯示,各型的黏蛋白在胰腺癌中陸續被發現表現量異常,然而黏蛋白第二十型(MUC20) 在胰腺癌中扮演的角色仍未知。
本篇研究結果如下:胰腺癌組織的免疫染色結果與臨床特徵之相關性統計顯示,MUC20表現量高與低病人存活率及術後局部復發率呈正相關。血清剝奪、低氧及酸性環境皆能誘發胰腺癌細胞中MUC20的表現量。以小分子干擾核糖核酸抑制胰腺癌細胞株HPAC及HPAF-II 的MUC20表現量,則由星狀細胞所誘發的HPAC及HPAF-II爬行及侵襲能力也隨之減弱。在腹腔、皮下及胰臟注射胰腺癌細胞的動物模式中,降低胰腺癌細胞MUC20的表現量可減緩其在免疫缺陷鼠體內的生長。磷酸化-受體酪氨酸激酶陣列 (Phospho-Receptor Tyrosine Kinase Array, p-RTK array) 和西方墨點法 (Western Blot) 的分析結果顯示,將胰腺癌細胞中MUC20的表現量降低可同時降低由肝細胞生長因子(Hepatocyte Growth Factor, HGF)所誘發的肝細胞生長因子受體之磷酸化 (Phospho-Hepatocyte Growth Factor Receptor, p-MET)。由HGF所誘發的胰腺癌細胞惡性表徵,可藉由降低其細胞內MUC20的表現量而將之抑制。免疫共沉澱 (co-immunoprecipitation, co-IP) 的實驗結果顯示,MUC20和MET間有實質上的交互作用。 總結:胰腺癌細胞中MUC20表現量降低而產生其惡性表徵減弱的現象,至少部分是由於HGF/MET訊息傳遞路徑受到抑制而導致,同時也顯現MUC20極有潛力成為治療性標靶。 Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic and acidic microenvironment and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71235 |
DOI: | 10.6342/NTU201801830 |
全文授權: | 有償授權 |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-107-1.pdf 目前未授權公開取用 | 3.06 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。