在腦部的神經膠質瘤中（Glioblastoma multiforme, GBM），多行性神經膠質母細胞瘤屬於最常見也是最致命且侵略的惡性腦腫瘤。相較於其他常見的癌症，最近幾十年在臨床上的試驗當中並無法有效的改善多行性神經膠質母細胞瘤生存率以及預後經常性復發情況。當病人被診斷出是罹患多行性神經膠質母細胞瘤時，通常壽命只剩下約2年的時間，即使手術切除腫瘤、放射和化學藥物治療同時複合治療，大多數仍舊因為極高復發率而死亡，因此找出原因和方法去應付多行性神經膠質母細胞瘤是目前非常重要的課題。我們實驗室已經建立的多行性膠質母細胞瘤轉基因小鼠模型 利用cDNA生物晶片技術我們發現，GDNF/RET信號路徑中下游的GFRA1和GFRA2都有大量表現在多行性神經膠質母細胞瘤的發展中。因此本篇的研究重點首先我們將GDNF/RET、GFRA1或GFRA2剃除時，是否可以有效抑制多行性神經膠質母細胞瘤的生長和移動。因此我們將多行性神經膠質母細胞瘤的細胞株做了GFRA1和GFRA2的基因敲落以降低基因的表現，並且做了一系列細胞功能性分析實驗，我們發現將GDNF/RET、GFRA1或GFRA2剃除時，可以有效抑制多行性神經膠質母細胞瘤的生長和移動。另外將我們的GBM小鼠投GDNF/RET抑制劑，我們證實GDNF/RET這條信號路徑如果被抑制之後，可以有效的降低多行性神經膠質母細胞瘤的生成。總結，我們的結果顯示GDNF / RET途徑可能是GBM治療的潛在治療靶點。

Glioblastoma multiforme (GBM) is the most common, deadly and aggressive brain tumor arising from glial cells. In contrast to other solid cancers, clinical trials in recent decades have not been effective to improve the survival rate and post-recurrence of GBM. When a patient is diagnosed with GBM. and went for resection of the tumor or combined chemotherapy, the prognosis of patients is still poor due to the relapse of the tumor. Indeed, the failed clinical trials with ineffective GBM treatment informed us that there is insufficient knowledge of the mechanisms underlying this lethal disease. To improve the outcomes for patients with GBM, our laboratory has established genetically modified mouse models of GBM. By using cDNA microarray analysis, we observed that GDNF/RET/GFRA1/GFRA2 signaling pathway was upregulated during GBM development. Therefore, this study aims to investigate the functional roles of GDNF/RET pathway in GBM progression, and test whether the inhibition of GDNF/GFRA pathway can block GBM development. Here we first knockdown of GFRA1 and GFRA2 in GBM cells to observe the decreased cell growth and migration in vitro. Lastly, we treated GBM mice with GDNF/RET inhibitors to show the significantly reduction of GBM formation in vivo. In summary. Our results suggest that the GDNF/RET pathway might be a potential therapeutic target for GBM treatment.

國立中山大學研究生學位論文審定書………………………i
中文摘要………………….…………….……………………ii
英文摘要……………………………….………………...….iii
縮寫……………………………………………………………iv
簡介……………………………………………………….……1
材料與方法……………………………………………….……5
結果…………………………………………………...………12
討論……………………………………………………...……18
圖表……………………………………………………...……21
參考資料……………………………………………………...41

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