Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy
Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy
复制标题
循环外泌体 miR-425-3p 对 NSCLC 对铂类化疗反应的预后作用
DOI：
10.1158/1055-9965.epi-18-0569
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Shu, Yongqian
中科院分区：
文献类型：
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作者：
Yuwen, Daolu;Ma, Yuzhu;Shu, Yongqian
背景资料：对于许多无铂类化合物禁忌症的非小细胞肺癌（NSCLC）患者，推荐使用含铂的二联化疗与第三代药物。不幸的是，这样的化疗的临床效果是有限的内在或获得resistance.Methods：循环exosomal miRNAs被分离出来，并用于执行HiSeq深度测序分析血清池样本铂耐药或铂敏感的患者，和6 exosomal miRNAs进一步验证其预测效用，通过qRT-PCR在170例晚期NSCLC患者的血清样本。功能获得和丧失实验阐明了临床相关miRNA的反应性调节作用。在203例接受铂类药物化疗的NSCLC患者中进行IHC分析，以评估肺癌组织中基础自噬与反应性之间的相关性。六种循环外泌体miRNA（miR-425-3p，miR-1273h，miR-4755-5p，miR-9-5p，miR-146a-5p，和miR-215- 5 p）的差异表达，与铂敏感患者相比，铂耐药患者的倍数变化最大。高miR-425- 3 p被证明是低反应性和低无进展生存期（PFS）的有效预测生物标志物。从机制上讲，miR-425- 3 p通过靶向AKT 1上调自噬水平，导致治疗反应降低。一致地，肺癌组织中高水平的基础自噬与NSCLC患者早期和晚期疾病阶段的低反应性相关。结论：我们的研究强调了循环外泌体miR-425- 3 p作为一种潜在的生物标志物，用于改善NSCLC患者对铂类化疗的临床反应预测。影响：这项研究提供了第一个证据，证明NSCLC患者来源的外泌体中的miR-425- 3 p可以作为预测对铂类化疗临床反应的标志物。
Background: Platinum-based doublets with a third-generation agent are the recommended option for many patients with non-small cell lung cancer (NSCLC) with no contraindications to platinum compounds. Unfortunately, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance.Methods: Circulating exosomal miRNAs were isolated and used to perform HiSeq deep-sequencing analyses on serum pool samples from platinum-resistant or platinum-sensitive patients, and six exosomal miRNAs were further validated for their predictive utility by qRT-PCR in 170 serum samples of patients with advanced NSCLC. Gain-and loss-of-function experiments clarified the responsiveness regulating role of the clinically relevant miRNA. IHC analyses were performed to evaluate the association between basal autophagy in lung cancer tissues and responsiveness in 203 patients with NSCLC receiving platinum-based chemotherapy.Results: Six circulating exosomal miRNAs (miR-425-3p, miR-1273h, miR-4755-5p, miR-9-5p, miR-146a-5p, and miR-215-5p) were found to be differentially expressed with the largest fold change in platinum-resistant patients compared with platinum-sensitive patients. High miR-425-3p proved to be a potent predictive biomarker for low responsiveness and poor progression-free survival (PFS). Mechanistically, miR-425-3p upregulated the autophagic levels via targeting AKT1, leading to the decrease in therapeutic response. Concordantly, high levels of basal autophagy in lung cancer tissues correlate with low responsiveness in patients with NSCLC within the early and advanced disease stages.Conclusions: Our study highlights circulating exosomal miR-425-3p as a potential biomarker for improved predictions of the clinical response to platinum-based chemotherapy in patients with NSCLC.Impact: This study provides the first evidence that miR-425-3p in NSCLC patient-derived exosomes can be a marker for predicating the clinical response to platinum-based chemotherapy.