Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, People's Republic of China.
Lianyungang Clinical College of Nanjing Medical University, Lianyungang, Jiangsu, People's Republic of China.
Int J Nanomedicine. 2021 Sep 16;16:6329-6343. doi: 10.2147/IJN.S321720. eCollection 2021.
Anlotinib resistance is a challenge for advanced non-small cell lung cancer (NSCLC). Understanding the underlying mechanisms against anlotinib resistance is of great importance to improve prognosis and treatment of patients with advanced NSCLC.
RT-qPCR assay was used to assess the level of miR-136-5p in anlotinib-resistant NSCLC cells and exosomes derived from anlotinib-resistant NSCLC cells. In addition, miR-136-5p level in tumor tissues from patients who exhibited a poor response to anlotinib therapy and patients who were therapy naïve or patients who exhibited a positive response to anlotinib therapy was detected by RT-qPCR assay.
In this study, we found that high levels of plasma exosomal miR-136-5p is correlated with clinically poor anlotinib response. In addition, anlotinib-resistant NSCLC cells promoted parental NSCLC cell proliferation via transferring functional miR-136-5p from anlotinib-resistant NSCLC cells to parental NSCLC cells via exosomes. Moreover, exosomal miR-136-5p could endow NSCLC cells with anlotinib resistance by targeting PPP2R2A, leading to the activation of Akt pathway. Furthermore, miR-136-5p antagomir packaging into anlotinib-resistant NSCLC cell-derived exosomes functionally restored NSCLC cell anlotinib sensitivity in vitro. Animal studies showed that A549/anlotinib cell-derived exosomal miR-136-5p agomir promoted A549 cell anlotinib resistance in vivo.
Collectively, these findings indicated that anlotinib-resistant NSCLC cell-derived exosomal miR-136-5p confers anlotinib resistance in NSCLC cells by targeting PPP2R2A, indicating miR-136-5p may act as a potential biomarker for anlotinib response in NSCLC.
安罗替尼耐药是晚期非小细胞肺癌（NSCLC）的一个挑战。了解针对安罗替尼耐药的潜在机制对于改善晚期 NSCLC 患者的预后和治疗非常重要。
使用 RT-qPCR 测定评估安罗替尼耐药 NSCLC 细胞和源自安罗替尼耐药 NSCLC 细胞的外泌体中的 miR-136-5p 水平。此外，通过 RT-qPCR 测定检测对安罗替尼治疗反应不佳的患者、未经治疗的患者或对安罗替尼治疗反应阳性的患者的肿瘤组织中的 miR-136-5p 水平。
在这项研究中，我们发现高水平的血浆外泌体 miR-136-5p 与临床安罗替尼反应不良相关。此外，安罗替尼耐药 NSCLC 细胞通过外泌体将功能性 miR-136-5p 从安罗替尼耐药 NSCLC 细胞转移至亲本 NSCLC 细胞，从而促进亲本 NSCLC 细胞增殖。此外，外泌体 miR-136-5p 可以通过靶向 PPP2R2A 赋予 NSCLC 细胞对安罗替尼的耐药性，从而激活 Akt 通路。此外，miR-136-5p 拮抗剂包装到安罗替尼耐药 NSCLC 细胞衍生的外泌体中可在体外恢复 NSCLC 细胞对安罗替尼的敏感性。动物研究表明，A549/安罗替尼细胞衍生的外泌体 miR-136-5p 激动剂在体内促进 A549 细胞对安罗替尼的耐药性。
综上所述，这些发现表明安罗替尼耐药 NSCLC 细胞衍生的外泌体 miR-136-5p 通过靶向 PPP2R2A 赋予 NSCLC 细胞对安罗替尼的耐药性，表明 miR-136-5p 可能作为 NSCLC 患者对安罗替尼反应的潜在生物标志物。
