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非小细胞肺癌中 EGFR-TKIs 获得性耐药通过 UHRF1/DNMT1 复合物促进 NF-κB 活性从而介导 MUC17 的表观遗传下调。

Acquired resistance to EGFR-TKIs in NSCLC mediates epigenetic downregulation of MUC17 by facilitating NF-κB activity via UHRF1/DNMT1 complex.

机构信息

Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.

Department of Endoscopic Diagnosis and Treatment, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, China.

出版信息

Int J Biol Sci. 2023 Jan 9;19(3):832-851. doi: 10.7150/ijbs.75963. eCollection 2023.

DOI:10.7150/ijbs.75963
PMID:36778111
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9910003/
Abstract

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has brought significant benefits to non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most patients eventually develop acquired resistance after treatment. This study investigated the epigenetic effects of mucin 17 (MUC17) in acquired drug-resistant cells of EGFR-TKIs. We found that GR/OR (gefitinib/osimertinib-resistance) cells enhance genome-wide DNA hypermethylation, mainly in 5-UTR associated with multiple oncogenic pathways, in which GR/OR cells exerted a pro-oncogenic effect by downregulating mucin 17 (MUC17) expression in a dose- and time-dependent manner. Gefitinib/osimertinib acquired resistance mediated down-regulation of MUC17 by promoting DNMT1/UHRF1 complex-dependent promoter methylation, thereby activating NF-κB activity. MUC17 increased the generation of IκB-α and inhibit NF-κB activity by promoting the expression of MZF1. results also showed that DNMT1 inhibitor (5-Aza) in combination with gefitinib/osimertinib restored sensitivity to OR/GR cells. Acquired drug resistance of gefitinib/osimertinib promoted UHRF1/DNMT1 complex to inhibit the expression of MUC17. MUC17 in GR/OR cells may act as an epigenetic sensor for biomonitoring the resistance to EGFR-TKIs.

摘要

表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKIs) 的治疗为携带 EGFR 突变的非小细胞肺癌 (NSCLC) 患者带来了显著的获益。然而，大多数患者在治疗后最终会产生获得性耐药。本研究探讨了粘蛋白 17 (MUC17) 在 EGFR-TKIs 获得性耐药细胞中的表观遗传效应。我们发现，GR/OR（吉非替尼/奥希替尼耐药）细胞增强了全基因组 DNA 超甲基化，主要是在与多种致癌途径相关的 5'-UTR 中，其中 GR/OR 细胞通过以剂量和时间依赖的方式下调粘蛋白 17 (MUC17) 的表达发挥致癌作用。吉非替尼/奥希替尼获得性耐药通过促进 DNMT1/UHRF1 复合物依赖性启动子甲基化来下调 MUC17，从而激活 NF-κB 活性。MUC17 通过促进 MZF1 的表达增加 IκB-α 的产生并抑制 NF-κB 活性。结果还表明，DNMT1 抑制剂（5-Aza）与吉非替尼/奥希替尼联合使用可恢复 OR/GR 细胞对药物的敏感性。吉非替尼/奥希替尼获得性耐药促进 UHRF1/DNMT1 复合物抑制 MUC17 的表达。GR/OR 细胞中的 MUC17 可能作为一种表观遗传传感器，用于监测对 EGFR-TKIs 的耐药性。

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2
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J Exp Clin Cancer Res. 2022 Mar 3;41(1):82. doi: 10.1186/s13046-022-02298-1.
3
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Front Immunol. 2025 Jun 27;16:1608140. doi: 10.3389/fimmu.2025.1608140. eCollection 2025.
4
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5
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