2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643949摘要：肺癌為台灣地區致死率最高的癌症，並且台灣民眾因肺癌而死亡的增加速度已是世界之最。僅管目前早期診斷與標準治療上已有顯著進步，但肺癌被診斷出時往往已在後期，並且預後極差，平均5年存活率只在15%左右。雖然抽煙為肺癌的主要危險因子，但也僅20%左右的抽煙者罹患肺癌。再者，正常支氣管上皮細胞轉變成肺癌的過程需許多基因的損傷。雖然有些基因，例如EGFR、KRAS、PI3K、p53等，已被報導與肺癌形成有關，但詳細的機轉仍不清楚。在我們先前對非吸煙女性肺癌病患的基因體研究中發現，semaphorin (SEMA)家族的許多基因，例如SEMA3B、 SEMA3G、SEMA5A、SEMA6A及 SEMA6D，其基因表現量都很顯著地降低。功能性分析也顯示，軸突指引訊息及Ephrin受體訊息是前三個最顯著的功能。不過，SEMA基因在肺癌上的角色，知道的卻很少。因為這些指引分子大體上是控制細胞的轉移及附著，故我們假設這些基因可能參與肺癌的形成機轉。為了證明我們的假設，我們提議進行下列實驗以達成的目標包括：第一、藉大量表現semaphorin基因於肺癌細胞株中來探討這些基因於肺癌生成上的作用；第二、利用微陣列來探討semaphorin基因於肺癌生成的分子機轉；第三、利用裸鼠實驗模型來進一步探討semaphorin基因於體內功能上所扮演的角色。利用基因學技術、功能測試與微陣列分析，本計劃能讓我們了解Semaphorin基因，在肺癌細胞的功能及在基因機轉上扮演何種角色。藉由更清楚地了解此疾病形成與演變的分子機轉，有助於我們發展個別針對肺癌的治療方式。<br> Abstract: Lung cancer is the leading cause of cancer death in Taiwan. The increase of lung cancer mortality rate in Taiwan has become the highest in the world. Despite advances in early detection and standard treatment, lung cancer is still often diagnosed at an advanced stage and has a poor prognosis, with less than 15% of overall 5-year survival rate. Although smoking is the major risk factor for lung cancer, only < 20% smokers have lung cancer. Furthermore, transforming normal bronchial epithelial cells to lung cancer requires a number of genetic molecular lesions. Although several genes, such as EGFR, KRAS, PI3K, p53, etc., have been reported to be involved in lung tumorigenesis, the detail mechanisms still remain unclear. In our previous genomic study on non-smoking female lung cancer patients, we identified that several genes in semaphorin (SEMA) family (e.g. SEMA3B, SEMA3G, SEMA5A, SEMA6A, and SEMA6D) were very significantly down-regulated. Functional analysis also revealed that genes involved in axonal guidance signaling and Ephrin receptor signaling were in the top three enriched functional categories. However, little is known about the role of SEMA genes in the lung cancer. Because these guidance molecules act in general to regulate cell migration and adhesion, we hypothesize that they are involved in mechanisms of disease progression in lung carcinogenesis. In order to prove our hypothesis, we propose to conduct experiments with the following specific aims:1) To investigate the effect of semaphorin genes in lung carcinogenesis by over-expressing SEMA genes in human lung cancer cells;2) To understand the molecular mechanisms of semaphorin genes in lung carcinogenesis by microarray analysis;3) To further characterize the functional roles of semaphorin genes in athymus nude mouse model.Using genetic approach, functional assays, and microarray analysis, this study will allow us to get an insight of the functional roles and genetic mechanisms of semaphorin gene family in lung cancer. By a better understanding of the molecular origins and evolution of the disease, we hope to contribute in developing a more specific therapeutic regime to treat lung cancer.肺癌轉移軸突傳導因子微陣列lung cancermetastasissemaphorinmicroarray