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標題: | FOXC1在非小細胞肺癌EGFR-TKI抗藥性之研究 Role of FOXC1 in EGFR-TKI Resistance of Non-Small Cell Lung Cancer |
作者: | Pin-Jyun Chen 陳品君 |
指導教授: | 陳青周 |
關鍵字: | 表皮生長因子受體-酪胺酸激?抑制劑,繼發抗藥性,FOXC1蛋白, EGFR-TKI,acquired resistance,FOXC1, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | EGFR activating mutation在亞洲地區之非小細胞肺癌病患約佔60%,EGFR-TKI可治療這類型之病患,但治療9-12個月後會產生Acquired resistance,因此探討EGFR-TKI抗藥性之機轉以克服抗藥性是重要之課題。
我們發現HCC827/IR (Iressa resistance) 與H1975/AR (AZD9291 resistance) 細胞均具Epithelial mesenchymal transition (EMT) 之特性,即E-cadherin表現降低與Vimentin表現增加、細胞移動能力增加。以RNA sequencing分析兩株抗藥性細胞,發現轉錄因子FOXC1之表現均增加,抑制細胞FOXC1之表現可恢復對TKI之敏感性,細胞之生長速度與遷移能力下降,亦可降低癌幹細胞性質。以Gene ontology分析與細胞遷移相關之基因,發現Rho家族蛋白RhoGDI2在抗藥性細胞表現降低,而抑制FOXC1會增加RhoGDI2之表現,並發現FOXC1會結合至RhoGDI2之promoter,抑制RhoGDI2之表現會增加細胞之遷移能力,顯示FOXC1會透過結合至RhoGDI2之promoter而抑制其表現。以Kaplan Meier Plotter分析肺腺癌病人分別在FOXC1高表現和RhoGDI2低表現中具較差預後。因此,推斷FOXC1可能可成為對抗非小細胞肺癌抗藥性之標的。 Epidermal growth factor receptor (EGFR)-activating mutation is the most common driver oncogene in lung adenocarcinoma in East Asia. So far, Tyrosine kinase inhibitors (TKIs) have been regarded as the preferred treatment for advanced lung adenocarcinoma harboring activating mutation in EGFR. However, acquired resistance often develops after treatment within 9-12 months. It is important to elucidate its underlying mechanism to improve the treatment. We establish two TKI-resistant NSCLC cell lines, and find that the expression of FOXC1, which is a transcriptional factor, is up-regulated in TKIresistant cells. FOXC1 knockdown not only restores the sensitivity to TKI but decreases cell proliferation and migration. FOXC1 knockdown also inhibits the cancer stem cells signature. We further examine several genes that are associated with motility and adhesion in TKI-resistant cell lines, and find that RhoGDI2 is up-regulated and its promoter activity is increased when FOXC1 is knocked down. We also clarify that FOXC1 binds to the promoter region of RhoGDI2 by ChIP assay, and RhoGDI2 knockdown increases cell migration. These data indicate that FOXC1 can bind to the promoter of RhoGDI2 to inhibit its expression. In Kaplan Meier Plotter database, high expression of FOXC1 and low expression of RhoGDI2 are related to poor patients prognosis. Therefore, FOXC1 might be an oncotarget in TKI-resistant NSCLC cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20483 |
DOI: | 10.6342/NTU201703677 |
全文授權: | 未授權 |
顯示於系所單位: | 藥理學科所 |
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