NF-κB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers.
NF-κB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers.
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NF-kappa B 驱动的 EHD1 改善有助于 EGFR 突变肺癌的厄洛替尼耐药
DOI：
10.1038/s41419-018-0447-7
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发表时间：
2018-04-01
影响因子：
9
通讯作者：
Cai L
中科院分区：
文献类型：
--
作者：
Wang X;Yin H;Zhang H;Hu J;Lu H;Li C;Cao M;Yan S;Cai L
对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）（如吉非替尼和厄洛替尼）的获得性耐药是EGFR突变阳性非小细胞肺癌（NSCLC）治疗的关键障碍。EHD 1是一种C-末端Eps 15同源结构域（EHD）家族的蛋白质，在调节内吞再循环中发挥作用，但涉及EGFR-TKI耐药性和癌症干性的机制细节仍不清楚。在这里，我们发现较低的EHD 1表达改善了EGFR-TKI的敏感性，这与较低的CD 133表达和NSCLC患者的无进展生存率一致。EHD 1的过表达在体外和体内显著增加了肺癌细胞对厄洛替尼的耐药性和干细胞性。此外，我们证明miR-590靶向EHD 1的3′-UTR，并受NK-κB调控，导致EHD 1表达下调，增加厄洛替尼敏感性，并抑制NSCLC肿瘤干细胞样特性。我们发现EHD 1是EGFR-TKI耐药和肺癌干细胞样细胞表型的重要因素，这些结果表明，靶向NF-κB/miR-590/EHD 1通路对获得性EGFR-TKI耐药的EGFR突变型NSCLC患者具有潜在的治疗前景。
Acquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients. The overexpression of EHD1 markedly increased erlotinib resistance and lung cancer cell stemness in vitro and in vivo. Moreover, we demonstrated that miR-590 targeted the 3′-UTR of EHD1 and was regulated by NK-κB, resulting in downregulated EHD1 expression, increased erlotinib sensitivity and repressed NSCLC cancer stem-like properties in vitro and in vivo. We found that EHD1 was an important factor in EGFR-TKI resistance and the cancer stem-like cell phenotype of lung cancer, and these results suggest that targeting the NF-κB/miR-590/EHD1 pathway has potential therapeutic promise in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance.
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影响因子：
9.2
作者：
Dunphy, JL;Moravec, R;Casanova, JE
通讯作者：
Casanova, JE
影响因子：
20.4
作者：
Ludovini, Vienna;Bianconi, Fortunato;Crino, Lucio
通讯作者：
Crino, Lucio
哺乳动物Eps15同源结构域1通过诱导上皮间质转化促进非小细胞肺癌转移
影响因子：
--
作者：
Meng Q;Xing Y;Ren T;Lu H;Xi Y;Jiang Z;Hu J;Li C;Sun L;Sun D;Cai L
通讯作者：
Cai L
影响因子：
45.3
作者：
Keedy, Vicki Leigh;Temin, Sarah;Giaccone, Giuseppe
通讯作者：
Giaccone, Giuseppe
影响因子：
7.5
作者：
Inamura, Kentaro;Takeuchi, Kengo;Ishikawa, Yuichi
通讯作者：
Ishikawa, Yuichi