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標題: 利用過量表現人類血管內皮生長因子A165基因轉殖鼠模式探討其肺部癌化機制
The Mechanisms of Lung Carcinogenesis in Human VEGF-A165 Overexpressed Transgenic Mice.
作者: 周郁青
Chou, Yu-Ching
關鍵字: VEGF;血管新生;angiogenesis;lung cancer;cDNA microarray;肺腺癌;基因轉殖動物;生物晶片
出版社: 生命科學系所
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非小細胞肺癌(non-small cell lung cancer;NSCLC) 與其它惡性腫瘤一樣,其發生和轉移均依賴於新的血管生成。血管內皮生長因子(vascular endothelial growth factor-A165;VEGF-A165) 已被證明可以誘導血管內皮細胞的增生、促進細胞遷移以及抑制細胞凋亡;同時VEGF-A165亦可提高血管的通透性進而促使新血管的生成,因此在生物發育以及癌症生成過程,均扮演著重要的角色。本研究利用小鼠肺部支氣管上皮分泌蛋白(clara cell secretory protein;CCSP) 之基因為啟動子,銜接人類血管內皮新生因子-A165 【ccsp-Vegf-A165-sv40 poly(A)】,培育出肺部專一性表現的基因轉殖小鼠系統作為肺癌的動物模式,以cDNA基因晶片進行基因轉錄體(transcriptomic) 分析,探究與VEGF-A165誘導腫瘤生成之相關因子。在病理切片觀察中,歸類出不同肺部損傷程度之檢體,並使用組織免疫染色法與西方墨點法證明與hVEGF-A165蛋白表現量呈正相關。我們更進一步使用生物晶片分析系統偵測鼠肺檢體,挑選出與細胞凋亡(3個)、血管新生(3個)、細胞生長週期(2個)與細胞致癌基因(2個)等相關基因群,經由生物反應路徑資料庫暨分析平台(Ingenuity Pathway Analysis;IPA)系統搜尋,找出此基因群在訊息傳遞中與肺腺癌生成的相關性,並在RNA與蛋白表現的層級上,驗證其結果。另外,我們亦使血管影像分析系統(Angiogenesis Image Analyzer;AIA)與雞蛋尿囊絨毛膜試驗(Chick Chorioallantoic Membrane;CAM)證實其基因轉殖鼠肺部組織卻可以誘發血管新生,進而導致其肺部趨向癌化。根據我們的研究,證實專一過量表現hVEGF-A165的確會使十二月齡以上鼠肺誘發血管新生,進而造成損傷與癌化。

Lung cancers are one of the most common cancers in the world. Lung cancers are classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). The vascular endothelial growth factor-A165 (VEGF-A165) induces endothelial cell proliferation , promotes cell migration, and inhibits apoptosis. VEGF-A165 induces angiogenesis as well as permeabilization of blood vessels, and plays a central role in the regulation of vasculogenesis in vascular development and cancer. In this study, we investigated an over 12-month-old lung-specific VEGF-A165 overexpressed transgenic mice model which constructed ccsp-Vegf-A165-sv40 poly(A) transgene as a subject matter. In pathological section, we referred specimen to different levels of lung lesion, which showed a positive correlation with the expression levels of hVEGF by immunohistochemistry and western blot. Furthermore, we used an Angiogenesis Image Analyzer (AIA) and Chick Chorioallantoic Membrane (CAM) to demonstrate that angiogenesis phenomenon was higher in transgenic mice than that of wild-type mice. Moreover, we performed cDNA microarray to exam gene expressions on lung samples of transgenic mice. We also analyzed the differences in these genes, then further indentified the relevance between the genes and lung adenocarcinoma by Ingenuity Pathway Analysis(IPA). The relative gene clusters of cell proliferation, cell cycle, cell metastasis, carcinogenesis and angiogenesis were chosen to elucidate by RT-PCR, Q-PCR and western blots. The data showed that not only hvegf-A165 but also kdr, nrp-1, egfr, cyclin B1, cdc2, mmp9, brca1 and myc are up-regulated. These results were also the same as increasing in CDC2 phosphorylation signaling pathway. Base on our study, the expression of pulmonary tumorigenesis factors are increased significantly dependent on VEGF-A165 overexpression.
其他識別: U0005-3112200814095500
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