探討L1細胞黏附分子於舌鱗狀細胞癌中所扮演之角色; Role of L1 Cell Adhesion Molecule in Tongue Squamous Cell Carcinoma

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题名:	探討L1細胞黏附分子於舌鱗狀細胞癌中所扮演之角色;Role of L1 Cell Adhesion Molecule in Tongue Squamous Cell Carcinoma
作者:	洪曉貞;Shiao-Chen Hung
贡献者:	中國醫藥大學：癌症生物學研究所
关键词:	口腔癌;Ｌ1細胞黏附分子;Oral cancer;L1-CAM
日期:	2009-07-09
上传时间:	2009-08-12 13:50:03 (UTC+8)
摘要:	摘要: 根據行政院衛生署的統計，目前口腔癌排行國人癌症前十大死因中的第六位。其原因不外乎口腔內所發生的癌前病變並不顯著，所以經常被忽略，隨著病程進展，口腔癌有可能經淋巴轉移而導致頸部淋巴結的腫大。目前導致口腔癌化的機制仍有待了解。另一方面，L1細胞黏附分子為大腦和神經組織在發育過程中，一個不可或缺的分子。目前越來越多的研究報告指出，L1細胞黏附分子會在許多的癌細胞中有過度表現的情況，例如大腸直腸癌或是乳癌等。而L1細胞黏附分子過度表現的情況和癌細胞癌化的進程具有相關性且也代表著病患有較差的預後。我們的研究目標是去探討L1細胞黏附分子在舌鱗狀細胞癌的癌化過程中所扮演的角色，並且希望藉此瞭解其中的調控機制。首先，在方法上，我們利用西方墨點法，流式細胞儀以及酵素連結免疫吸附分析發現L1細胞黏附分子在較為惡性的舌鱗狀細胞癌的細胞株中有過度表現的情況。接下來，我們利用建立基因改造模型(Genetically manipulation)的舌鱗狀細胞癌，來達到L1細胞黏附分子在舌鱗狀細胞癌表現量的差異。我們主要利用反轉錄病毒及慢病毒為載體，攜帶L1細胞黏附分子的基因和L1 siRNA來達到過度表達或干擾此蛋白質的表現。體外實驗結果的部份，我們發現L1細胞黏附分子的表現和舌鱗狀細胞癌的細胞黏附能力以及細胞的能動行具有極大的關聯性。除此之外，藉由上皮─間質轉化(epithelial-mesenchymal transition)的標誌的表現與否，包括E-cadherin，Vimentin，Fibronectin的改變我們發現，在舌鱗狀細胞癌中，L1細胞黏附分子會藉由上皮─間質轉化的方式去調控細胞能動性和貼附的能力。另一方面，在動物模式發現當降低L1細胞黏附分子的表現時，腫瘤的生長及轉移能力則明顯地被抑制。同時也發現降低L1細胞黏附分子的表現時，老鼠的存活率明顯地增加。由我們的研究結果可以發現，L1細胞黏附分子可以藉由上皮─間質轉化來調控舌鱗狀細胞癌的癌化過程。除此之外，針對口腔癌的治療，L1細胞黏附分子也許可以當作一個新的分子標靶治療。 Abstract: Oral cancer is one of the top 10 leading causes of death from cancer in Taiwan. This disease is characterized by poor prognosis and low survival rate. The molecular mechanisms of oral cancer progression are not well understood. Overexpression of L1 cell adhesion molecular (L1-CAM) has been found in many human carcinomas and is associated with tumor progression and poor prognosis. The aim of this study is to investigate the relationship between L1-CAM expression and tumor progression in tongue squamous cell carcinoma (TSCC) with a hope of understanding the molecular mechanisms of TSCC. The expression of L1-CAM in TSCC cell lines was determined by Western blotting, FACS, and ELISA analyses. Genetically manipulated TSCC stable cell lines with either over-expressed or down-regulated L1-CAM were generated by retroviral vector carrying L1-CAM cDNA transfection or lentiviral vector-mediated L1-CAM siRNA delivery, respectively. The resultant cell lines were determined and compared behavior changes including growth rate, migration and invasion in vitro using MTS and Transwell migration assay. We found that L1-CAM was detected in all testing TSCC cell lines (SAS, SCC4, SCC9, SCC25) with a variable expression level and negligible in human normal oral fibroblast cells. Over-expressed L1-CAM in L1-CAM low-expressing SCC25 cells enhanced cell growth, migration, invasion and attachment on fibronectin. Conversely, knockdown L1-CAM in L1-CAM highly-expressing SCC4 cells resulted in decreased cell ability in adhesion and motility. Moreover, L1-CAM mediated cell motility was in accordance with increased E-cadherin and decreased Vimentin and Fibronectin expression, suggesting that L1-CAM is involved in epithelial-mesenchymal transition (EMT) of TSCC. Our results demonstrated the first time that L1-CAM conferred TSCC tumor progression through the pathway of EMT. These findings also suggested that L1-CAM is a promising molecular target for the treatment of oral cancer.
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