Naidu Srivatsava, Shi Lei, Magee Peter, Middleton Justin D, Laganá Alessandro, Sahoo Sudhakar, Leong Hui Sun, Galvin Melanie, Frese Kristopher, Dive Caroline, Guzzardo Vincenza, Fassan Matteo, Garofalo Michela
Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK.
Sci Rep. 2017 Nov 13;7(1):15441. doi: 10.1038/s41598-017-14843-6.
In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-β in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR-23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKβ, AKT2, ERK2 and KRAS itself. Of note, an inverse correlation between miR-23b cluster, miR-125a-5p and respective target genes was also found in vivo in a large dataset of lung adenocarcinoma samples. Furthermore, in vivo delivery of miR-23b cluster or miR-125a-5p significantly repressed tumour growth in a highly aggressive NSCLC circulating tumour cell (CTC) patient derived explant (CDX) mouse model. In conclusion, our finding sheds light on the PDGFR signaling and endorses the possibility to employ miR-23b cluster and miR-125a-5p as therapeutic tools to silence simultaneously a range of redundant pathways and main effectors of tumorigenesis in NSCLC.
在非小细胞肺癌（NSCLC）中，血小板衍生生长因子（PDGF）受体的改变是预后较差的标志物，而对这些受体进行有效靶向治疗尚未实现。在本研究中，我们探索了PDGFR调节的微小RNA，结果表明在NSCLC细胞中，miR-23b簇和miR-125a-5p会因PDGFR-α或PDGFR-β表达增加而下调。从机制上讲，这些微小RNA的表达受p53正向调节，受NF-κB p65负向调节。强制表达miR-23b簇或miR-125a-5p可增强NSCLC细胞的药物敏感性并抑制其侵袭性，这是通过沉默参与致癌KRAS和NF-κB信号通路的多个基因实现的，这些基因包括SOS1、GRB2、IQGAP1、RALA、RAF-1、IKKβ、AKT2、ERK2以及KRAS本身。值得注意的是，在一个大型肺腺癌样本数据集中，在体内也发现了miR-23b簇、miR-125a-5p与各自靶基因之间呈负相关。此外，在一个高度侵袭性的NSCLC循环肿瘤细胞（CTC）患者来源的移植瘤（CDX）小鼠模型中，体内递送miR-23b簇或miR-125a-5p可显著抑制肿瘤生长。总之，我们的研究结果揭示了PDGFR信号传导机制，并支持将miR-23b簇和miR-125a-5p用作治疗工具，以同时沉默NSCLC中一系列多余的信号通路和肿瘤发生的主要效应因子。
