Ligand-independent EphA2 contributes to chemoresistance in small-cell lung cancer by enhancing PRMT1-mediated SOX2 methylation.
Ligand-independent EphA2 contributes to chemoresistance in small-cell lung cancer by enhancing PRMT1-mediated SOX2 methylation.
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作者：
化疗耐药是小细胞肺癌（SCLC）临床治疗失败的关键。肿瘤干细胞在恶性肿瘤的治疗抗性中起关键作用。研究表明，促红细胞生成素产生的肝细胞A2（EphA 2）在肿瘤中的作用是复杂的。本研究旨在检验EphA 2的配体非依赖性激活通过增强SCLC中的干性来调节化学抗性的假设。我们验证了EphA 2在化学抗性亚系中以配体非依赖性方式而不是配体依赖性方式被激活。配体非依赖性EphA 2增强干细胞相关生物标志物（CD 44，Myc和SOX 2）的表达，加速上皮-间质转化（EMT）并增强自我更新以驱动SCLC的化学抗性，而P817 H突变体EphA 2中和内在功能。进行免疫共沉淀（co-IP）和GST-下拉实验以验证EphA 2与PRMT 1直接相互作用。此外，EphA 2增加PRMT 1的表达和活性。PRMT 1与SOX 2相互作用并使SOX 2甲基化，从而诱导SCLC的干性和耐药性。EphA 2的药理学抑制在临床前模型（包括患者来源的异种移植物（PDX）模型）中显示出与化疗的协同抗肿瘤作用。这些发现首次强调了EphA 2/PRMT 1/SOX 2途径通过促进干性诱导SCLC的化学抗性。EphA 2是SCLC治疗中的潜在治疗靶点。这项研究表明，配体非依赖性EphA 2诱导SCLC中的化学抗性。配体非依赖性EphA 2与PRMT 1直接相互作用，其增强干性以促进SCLC中的化学抗性，同时在R43处甲基化SOX 2。最后，EphA 2的抑制证实了体外和体内实验中的抗肿瘤作用。
Chemoresistance is the crux of clinical treatment failure of small‐cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin‐producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand‐independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand‐independent manner rather than a ligand‐dependent manner. Ligand‐independent EphA2 enhanced the expression of stemness‐associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial–mesenchymal transition (EMT) and reinforced self‐renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co‐immunoprecipitation (co‐IP) and GST‐pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti‐tumor effect with chemotherapy in preclinical models, including patient‐derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment. This study showed that ligand‐independent EphA2 induces chemoresistance in SCLC. Ligand‐independent EphA2 directly interacted with PRMT1, which augmented stemness to promote chemoresistance in SCLC while methylating SOX2 at R43. Finally, inhibition of EphA2 confirmed the anti‐tumor effect both in vitro and in vivo experiments.
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DOI：
10.1186/s13046-020-01783-9
发表时间：
2020-12-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Hu XT;Xing W;Zhao RS;Tan Y;Wu XF;Ao LQ;Li Z;Yao MW;Yuan M;Guo W;Li SZ;Yu J;Ao X;Xu X
通讯作者：
Xu X
影响因子：
4.7
作者：
Bahmad HF;Cheaito K;Chalhoub RM;Hadadeh O;Monzer A;Ballout F;El-Hajj A;Mukherji D;Liu YN;Daoud G;Abou-Kheir W
通讯作者：
Abou-Kheir W
EphA2-to YAP 通路驱动胃癌生长和治疗耐药
影响因子：
6.4
作者：
Huang, Changhao;Yuan, Weijie;Chen, Zhikang
通讯作者：
Chen, Zhikang
影响因子：
45.3
作者：
EVANS, WK;SHEPHERD, FA;DEBOER, G
通讯作者：
DEBOER, G
影响因子：
50.3
作者：
Binda E;Visioli A;Giani F;Lamorte G;Copetti M;Pitter KL;Huse JT;Cajola L;Zanetti N;DiMeco F;De Filippis L;Mangiola A;Maira G;Anile C;De Bonis P;Reynolds BA;Pasquale EB;Vescovi AL
通讯作者：
Vescovi AL