2018-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/711694摘要：表皮生長因子受器酪胺酸激酶抑制劑 (EGFR-TKIs)為目前常用的肺癌治療用藥。一些臨床報告指出，患者在用藥後，皮膚出現了紫斑情形。表皮生長因子受器的抑制可能會破壞血管壁的完整性，但詳細的作用機制並不清楚。我們先前的研究發現，EGFR-TKIs會減少血管內皮細胞的增生且具有劑量效應，也會抑制其MAPK路徑和EGFR的磷酸化。我們用晶片微陣列實驗和西方墨點法發現erlotinib會使血管內皮細胞高表現IQGAP1的RNA和蛋白質。IQGAP1高表現會減少跨血管內皮細胞層的電阻並增加血管內皮細胞層的通透性。因此，我們假設erlotinib會藉由增加IQGAP1的表現量，而改變血管內皮細胞黏著型連接的功能。 Erlotinib會增加血管內皮細胞IQGAP1表現的機轉還不是很清楚。我們假設erlotinib會藉由增加IQGAP1的SUMO 蛋白質修飾化，而使IQGAP1蛋白更穩定。我們也會探討IQGAP1對黏著型連接相關蛋白的表現量以及分佈位置的影響。因為使用外用類固醇藥膏或全身性頭孢子素抗生素治療，在臨床上對EGFR-TKIs引起的紫斑樣皮疹很有效，我們假設類固醇或全身性頭孢子素抗生素可以抑制IQGAP1導致VEGF引起的血管內皮細胞黏著破壞。因此，我們將研究類固醇或全身性頭孢子素抗生素改善erlotinib引起的血管障壁功能異常的效果。總結來說，本研究將探討表皮生長因子受器的路徑被阻斷後，會經由多種因素，包括IQGAP1，而使得血管障壁被破壞、表現出臨床上的紫斑皮膚炎的機轉，並提供轉譯醫學上之治療新機轉。<br> Abstract: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used as a treatment for advanced stage non-small cell lung cancer. There are some reports of EGFR-TKI-associated vascular adverse events. The disruption in normal EGFR pathway may give rise to impairment of integrity of the blood vessel walls. However, the exact mechanism of EGFR-TKI-induced vascular adverse events is still unknown. We revealed that EGFR-TKIs decreased the proliferation of HMEC-1s and HMVECs in a dose-dependent manner and also inhibited the MAPK pathway and EGFR phosphorylation. We examined the mRNA expression profile of erlotinib-treated HMEC-1 and identified IQGAP, as the most consistently upregulated transcript and protein. Increased IQGAP1 expression was associated with the decreased transendothelial electrical resistance and increased vascular permeability in vitro. We hypothesized that erlotinib induces adherens junction dysfunction by modulating the expression of IQGAP1 in vascular endothelial cells. The exact molecular mechanism by which erlotinib increased IQGAP1 expression in HMEC-1s is still unknown. We hypothesize that erlotinib may promote stabilization of IQGAP1 by increasing SUMOylation of IQGAP1. We will explore the effect of IQGAP1 on adherens junctional complex expression and localization. Because the purpuric drug eruptions caused by EGFR-TKIs frequently faded after being treated with topical steroid or systemic cephalosporins clinically, we speculate that glucocorticoids or cephalosporins may inhibit barrier dysfunction by preventing IQGAP1-related and VEGF-stimulated loss of cell-cell contacts. Hence, we will investigate the effects of glucocorticoids or cephalosporins on erlotinib-related barrier dysfunction. In conclusion, the disruption in EGFR pathway may contribute to impairment of integrity of the blood vessel walls through multiple factors including IQGAP1. This study will investigate its underlying mechanisms and also provide translational application in our clinical practice to treat purpuric drug eruptions.黏著型連接表皮生長因子受器表皮生長因子受器酪胺酸激酶抑制劑血管內皮細胞IQGAP1adherens junctionEGFR tyrosine kinase inhibitorendothelial cellIQGAP1