Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cell Death Dis. 2019 Mar 25;10(4):283. doi: 10.1038/s41419-019-1519-z.
Comparatively less toxic and more tolerated, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommendable for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. Some EGFR wild-type patients with specific biomarkers also show a response to the drug. TAZ is an oncogene closely associated with the therapeutic effect of EGFR-TKIs. However, this association remains to be clarified. This study aimed to clarify the mechanism through which TAZ sensitizes EGFR wild-type NSCLC to gefitinib. We used CCK-8 assays and in vivo experiments to investigate the influence of TAZ on gefitinib in EGFR wild-type NSCLC. To further validate the tumorigenic role of TAZ, we performed Human umbilical vein endothelial cell (HUVEC) tube formation and migration assays. Luciferase reporter assays, quantitative real-time PCR (qPCR), immunoblotting and Chromatin immunoprecipitation collaborated with qPCR illuminated the mechanism through which TAZ caused those phenotypes. The results showed TAZ promoted the angiogenesis of NSCLC cell lines and improved gefitinib sensitivity in EGFR wild-type NSCLC in vitro and in vivo. Luciferase reporter assays and ChIP-qPCR experiments showed TAZ upregulated AREG by promoting its transcription. EGFR signaling pathway was activated as TAZ was highly expressed. Rescue experiments were conducted to confirm the indispensable role of AREG in tumorigenesis and gefitinib sensitivity regulated by TAZ. Our study concluded that TAZ sensitized EGFR wild-type NSCLC to gefitinib through promoting amphiregulin transcription.
与其他药物相比，表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的毒性相对较低，患者耐受性更好，因此被推荐用于治疗存在 EGFR 敏感突变的晚期非小细胞肺癌（NSCLC）患者。部分 EGFR 野生型患者存在特定的生物标志物，也对该药物有反应。TEAD 结合蛋白（TAZ）是一种与 EGFR-TKIs 治疗效果密切相关的致癌基因。然而，这种关联仍有待阐明。本研究旨在阐明 TAZ 使 EGFR 野生型 NSCLC 对吉非替尼敏感的机制。我们使用 CCK-8 检测和体内实验研究了 TAZ 对 EGFR 野生型 NSCLC 中吉非替尼的影响。为了进一步验证 TAZ 的致癌作用，我们进行了人脐静脉内皮细胞（HUVEC）管形成和迁移实验。荧光素酶报告基因检测、实时定量 PCR（qPCR）、免疫印迹和染色质免疫沉淀与 qPCR 合作，揭示了 TAZ 引起这些表型的机制。结果表明，TAZ 促进了 NSCLC 细胞系的血管生成，并在体外和体内提高了 EGFR 野生型 NSCLC 对吉非替尼的敏感性。荧光素酶报告基因检测和 ChIP-qPCR 实验表明，TAZ 通过促进其转录而上调 AREG。由于 TAZ 高表达，EGFR 信号通路被激活。进行了挽救实验以确认 AREG 在 TAZ 调节的肿瘤发生和吉非替尼敏感性中不可或缺的作用。我们的研究得出结论，TAZ 通过促进 Amphiregulin 转录使 EGFR 野生型 NSCLC 对吉非替尼敏感。
