2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647083摘要：肺癌是許多國家癌症死因之首。台灣每年約有8000 例新肺癌病患，超過85%罹患非小細胞肺癌。隨著醫學的進步，肺癌的死亡率並未降低。近半的新肺癌病患屬於晚期肺癌，整體而言將近90%的病患存活不及二年。ADAM 是一群擁有disintegrin 和金屬蛋白酶區域的蛋白質家族。人類總共有25 個家族成員，參與細胞的蛋白質溶解、細胞接合、細胞融合與訊息傳遞。其中僅有1/3 具有觸酶活性，可以切割生長因子蛋白與細胞外間質蛋白。最近，有關ADAM 在癌症生成與行為過程所扮演角色的研究逐漸增多。而關於ADAM 與非小細胞肺癌的研究報告數量稀少，也無法取得具一致性的結果。我們先前利用實時間核酸聚合鏈鎖反應分析40 例肺癌的ADAM 基因表現，發現ADAM15 的表現與非吸菸肺癌及肺腺癌有關，並可能與存活有關聯。ADAM15 是ADAM 家族中唯一會與RGD integrin 接合者，其表現會影響血管生成，癌細胞生長與轉移。ADAM15 的cytoplasmic tail 具有不同變異體，可藉由細胞內訊息傳遞影響生物行為。我們假設ADAM15 在非小細胞肺癌的生成與轉移扮演重要角色。本三年計畫目的就在達成：1.經由實時間核酸聚合鏈鎖反應測量ADAM15 及其變異體在台灣肺癌的表現分布；2.並將ADAM15 變異體的表現量與肺癌臨床作關聯性分析；3.並利用過度表現ADAM15變異體之肺癌細胞株設法探討ADAM15 蛋白在肺癌生成與轉移的調控機轉。<br> Abstract: Lung cancer is the leading cause of death from cancer in many countries. In Taiwan, everyyear, about 8000 patients had newly diagnosed lung cancer. More than 85% of them contractnon-small cell lung cancer (NSCLC). Despite the continuing endeavors of scientists andclinicians, the cure rate remains low. About half of the newly diagnosed non-small cell lungcancer are in advanced stage (stage IIIB and IV), and nearly 90% of these patients die within2 years. The ADAMs (a disintegrin and metalloprotease) is a family of transmembraneproteases mediating a wide variety of activities including proteolysis, adhesion, cell fusionand signaling. Among 40 ADAMs, 25 were expressed in humans, and about one thirdencode active proteolytic activity. Catalytically active ADAMs cleave a variety of substrates,including growth factors and extracellular matrix proteins. Not until recently, investigatorsstarted to report the expression of ADAMs in cancers and their potential role incarcinogenesis. But in NSCLC, all the reports did not reach consistent result. Previously,using real-time quantitative PCR measuring the mRNA expression of 22 ADAMs in NSCLC,we identified a correlation of higher expression of ADAM15 in NSCLC of non-smokers(p=0.002, compared with ex- and current smokers) and in adenocarcinoma (p=0.038,compared with squamous cell ca). There was a tendency of worse survival in patientsbearing tumors with higher expression ADAM15. ADAM 15 is the only member of theADAM family with the integrin-binding motif Arg-Gly-Asp (RGD) in its disintegrin domain,and can influence the process of neovascularization, cancer proliferation and progression.ADAM15 also had many variant isoforms in cytoplasmic tails, which may drive differentbiological behavior through intracellular signaling. We hypothesize that the expression ofADAM15 and its variants had important roles in the carcinogenesis and progression ofNSCLC. In this three year study, we plan to achieve the following aims: 1. to characterizethe expression pattern of ADAM15 variants in NSCLC cell lines and NSCLC tissues ofTaiwan; 2. To correlate the expression pattern of ADAM15 variants with the clinicaloutcomes of NSCLC patients; 3. To clarify the role of different ADAM15 variants inregulating the behavior of NSCLC cells, including the interaction with ECM, interactionwith endothelial cells, cell proliferation, tumorigenicity and metastasis.擁有disintegrin和金屬蛋白酶區域的蛋白質家族間質金屬蛋白酶肺癌a disintegrin and metalloprotease familymatrix metalloproteaselung cancer