Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, People's Republic of China.
Mol Cancer. 2018 Feb 19;17(1):42. doi: 10.1186/s12943-018-0785-1.
ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance.
Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs).
ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity.
Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs.
ETS 变体基因 6（ETV6）是一种潜在的肿瘤抑制因子，在前列腺癌中受表皮生长因子受体（EGFR）信号的抑制。由于 EGFR 拮抗剂在去势抵抗性前列腺癌（CRPC）中似乎无效，我们旨在研究 ETV6 在耐药性发展中的作用。
通过 ChIP 和启动子报告测定验证 Etv6 靶基因。在人类临床数据集和组织样本中分析 ETV6 和 TWIST1 的相关性。迁移、侵袭和转移测定用于测量 ETV6-TWIST1 轴扰动后细胞的反应。在异种移植模型中进行增殖和肿瘤生长实验，以评估 EGFR-酪氨酸激酶抑制剂（TKIs）的药物敏感性。
ETV6 抑制 TWIST1 的表达，破坏 ETV6 会促进 TWIST1 依赖性恶性表型。重要的是，ETV6 是 EGFR-TKIs 抗增殖作用所必需的，部分原因是 ETV6 对 TWIST1 的抑制作用。我们还发现 EGFR-RAS 信号受到 ETV6 的紧密控制，支持其在 TKI 敏感性中的作用。
我们的研究表明，破坏 ETV6 有助于 EGFR-TKI 耐药，这可能是由于 TWIST1 的去抑制和 EGFR-RAS 信号的激活。我们的结果表明 ETV6 可能是预测 EGFR 靶向抗癌方法疗效的潜在标志物。TWIST1 抑制剂的联合治疗可能会增强 EGFR-TKIs 的抗增殖作用。
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