Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22414
標題: 過量表現人類血管內皮生長因子A165於基因轉殖小鼠肺部誘導腫瘤之生成
The Pulmonary Tumorigenesis Induced by Human VEGF-A165 Overexpression in the Lung Tissue of Transgenic Mice
作者: 黃彬武
Huang, Pin-Wu
關鍵字: 人類血管內皮生長因子A165
Human VEGF-A165
出版社: 生命科學系所
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摘要: 摘要 血管內皮成長因子(vascular endothelial growth factor, VEGF)家族可分為PIGF、VEGF-A、B、C、D、E共六個成員,其中VEGF-A可依mRNA不同剪接(alternative splicing)而分為各種異構型(isoforms),其中較常見的有VEGF-A206、VEGF-A189、VEGF-A165與VEGF-A121等四種異構型,而VEGF-A165 為主要執行功能之異構型。一般而言,VEGF-A具有促進血管增生(angiogenesis),增加血管壁通透性,促進細胞存活以及促進細胞遷移(cell migration)之功能,並於許多試驗中得知於腫瘤生長過程中VEGF-A表現量會聚集增加,具有增加腫瘤生長與促進腫瘤轉移(metastasis)之功能。Clara cell secretory protein (CCSP)係由一種稱為clara cell之非纖維性釋泌細胞所分泌的蛋白,Clara cell主要分佈於肺部支氣管及支氣管末梢之表皮部分,係為一種多功能性細胞,可以分化為許多肺部組織細胞以達到修補之功能;CCSP蛋白亦稱之為CC10、CC16或urine protein 1,係一種保護性蛋白,具有抑制免疫反應,降低發炎反應之效能。基於以上因素本試驗採用CCSP之啟動子銜接人類血管內皮成長因子A165[ccsp-Vegf-A165-sv40 poly(A)]之建構基因進行顯微原核注射,以建立一套於鼠肺支氣管上皮專一性表現之基因轉殖小鼠動物模式。於顯微原核注射後共產製出3隻基因轉殖小鼠,並以南方墨點法與聚合酶鏈鎖反應分析確認該Vegf-A165轉殖基因得以傳承於小鼠後代,進一步以反轉錄聚合酶鏈鎖反應與西方墨點法發現該Vegf-A165轉殖基因於小鼠肺部具有專一性之表現,並於病理組織切片分析結果發現於32隻Vegf-A165基因轉殖小鼠中,呈現支氣管表皮扁平化(96%)、支氣管表面細胞異常增生(93%)、發炎反應(43%)、纖維化(40%)、腺癌(18%)、囊胞(18%)等異常現象產生。進一步試驗結果顯示VEGF-A165具有促進ERK2磷酸化、survivin mRNA、cyclin D1 mRNA表現量增加,而該三種蛋白係為主要與細胞增生相關之蛋白,因此推測VEGF-A165係藉由活化ERK1/2之MAPK訊息傳導路徑依序增加cyclin D1 mRNA與survivin mRNA表現,以達到促使支氣管上皮細胞新生之目的。
Abstract The vascular endothelial growth factor (VEGF) family members consist of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PlGF). VEGF-A has at least nine subtypes due to the alternative splicing of a single gene and the the VEGF-A165 isoform plays a central role in vascular development. VEGF-A exhibits two major biological activities: One is the capacity to stimulate vascular endothelial cell proliferation, and the other is the ability to increase vascular permeability. VEGF-A also promotes the survival and migration of endothelial cells. VEGF-A and its receptor are involved in carcinogenesis, invasion and distant metastasis as well as tumor angiogenesis. Clara cell secretory protein (CCSP) is a protein that is secreted by nonciliated, nonmucous clara cells in the pulmonary airway. CCSP plays a protective role against pulmonary inflammatory response. CCSP is a potent natural immunosuppressor and anti-inflammatory agent. In this study, ccsp-Vegf-A165- sv40 poly(A) was constructed for the production of lung-specific overexpressing VEGF-A165 transgenic mice by microinjection. The results of PCR and Southern blot showed that there were three transgenic mice producted by that microinjection. Further, the results of Southern blot indicated there were the same patterns of the foreign gene within the genome of the transgenic founder mice and their offsprings. The data showed that Vegf-A165 mRNA can be expressed specifically in the lung tissue of the transgenic mice. And the results of Western blot also showed that the VEGF-A165 can be expressed in the lung tissue of the transgenic mice. In the histopathologic slides of the lung tissue in the transgenic mice, it seemed that VEGF-A165 overexpression can induce bronchial epithelium flattened(96%), abnormal proliferation of cells on bronchial epithelium(93%), inflammation(43%), fibrosis(40%), adenoma(18%) and cyst(18%) in the total examination of 32 transgenic mice. Further, the results showed that VEGF-A165 can promote phosphorylation of ERK2, increase the expression of cyclin D1 and survivin mRNA. All of the above suggest that VEGF-A165 induced the proliferation of cells on the bronchial epithelium of the transgenic mice through ERK1/2 MAPK pathway.
URI: http://hdl.handle.net/11455/22414
其他識別: U0005-2508200610422500
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2508200610422500
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