2016-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655715摘要：肺癌是許多國家癌症死因之首，超過 85% 為非小細胞肺癌 (NSCLC)。雖然醫學日益進步，但肺癌死亡率並未降低，因此發現肺癌新的治療標的及診斷標誌和改善目前治療方式是克不容緩的。ADAMs [a disintergrin and metalloprotease] 屬於穿膜金屬蛋白酶家族之一員，透過裁切不同的受質進而調控多種生理和病理功能。我們先前分析22個ADAMs的表現，ADAM15的表現與NSCLC有顯著相關。過去文獻指出，ADAM15和乳癌及攝護腺癌有關，然而其在NSCLC的表現意見分歧，ADAM15在細胞外部酵素活性並未參與HER3-EGFR路徑所導致NSCLC形成且其他ADAM15功能性domain對於導致NSCLC影響仍然未知。ADAM15有六種變異體，其差異只在擁有不同SH3結合motif數目的胞內domain。在乳癌中，較長ADAM15變異體表現較高且和數種擁有SH3 domain的蛋白結合，然而，其中詳細致癌機轉仍然未明。我們的結果已知最長的ADAM15變異體在較惡性NSCLC細胞株及人類肺癌檢體中表現量高，且透過和擁有SH3 domain的Grb2結合而促進NSCLC的增生。我們亦發現ADAM15和其他擁有SH3 domain的NPHP1, RASA1 及 PTK6結合，可能和NSCLC的惡化相關。因此，我們假設ADAM15和其他擁有SH3 domain的蛋白結合所引起的胞內訊息在NSCLC致病過程的數種機轉中扮演重要角色，最長的ADAM15變異體可以當成NSCLC診斷標誌，抑制ADAM15引起的胞內訊號可以應用在NSCLC的臨床治療上。本研究的結果可以擴充之前的研究成果，亦將提供治療NSCLC一個新的概念。 <br> Abstract: Lung cancer is the leading cause of cancer death worldwide and more than 85% is non-small cell lung cancer (NSCLC). Despite the continuing endeavors of scientists and clinicians, the cure rate remains low. Therefore, there is still an unmet need to discover novel therapeutic targets and diagnostic marks as well as improve existing treatment of NSCLC. The ADAMs (a disintegrin and metalloprotease) is a family of transmembrane metalloprotease mediating multiple physiological and pathological functions through cleavage a variety of substrates, including growth factors and extracellular matrix proteins. Like matrix metalloproteinases, the elevated expression and activation of ADAMs have been reported in many human cancers. Previously, we analyzed 22 ADAMs expressions in NSCLC. The expression of ADAM15 was significantly correlated with non-smoking NSCLC and adenocarcinima. Through extracellular metalloprotease activity, ADAM15 mediates multiple physiological function as well as tumorigenic processes in breast and prostate cancer. The expression of ADAM15 in NSCLC has been reported with controversial results. Furthermore, the external enzymetic activity of ADAM15 doesn’t involve in the HER3-epidermal growth factor receptor pathways in tumorigenesis of NSCLC. There has no information about other functional domains of ADAM15 are participated in tumorigenesis of NSCLC. ADAM15 has six variants which are only different in cytosolic domian with different number of Src homology (SH) 3 binding motif. In breast cancer, longer ADAM15 variant highly expresses in tumor and associates with multiple SH3 domain containing protein. However, the detail mechanism of ADAM15-mediated intracellular signaling in tumorigenesis remains unclear. According to our preliminary data, the longest ADAM15 variant overexpressed in malignant NSCLC cell line and human lung cancer specimen as well as promoted the proliferation in NSCLC via association with a SH3 domain containing protein Grb2. Our immunoprecipitation results revealed other SH3 domain containing protein such as NPHP1, Ras p21 protein activator 1 and protein tyrosine kinase 6 interact with ADAM15 and may mediated the progression of NSCLC. Therefore, we hypothesized that interaction ADAM15 with other cytosolic SH3 domain containing proteins also play a crucial role in tumorigenesis of NSCLC. In this three year study, we plan to expand the preliminary findings via finish the following aims: 1. To clarify the roles of ADAM15 cytosolic domain-modified intracellular signaling in multiple tumorigenic ability in NSCLC. 2. To identify the longest cytosolic domain of ADAM15 as a diagnostic marker of NSCLC. 3. To apply the inhibition of ADAM15-mediated cytosolic signaling as a clinical therapeutic way for NSCLC. The findings of this study may provide a new concept in therapy of NSCLC and even apply for therapies of other human cancers.非小細胞肺癌ADAM15SH3 domainnon-small cell lung cancer (NSCLC)a disintegrin and metalloprotease 15 (ADAM15)Src homology (SH)3 domain