Platinum-based drugs such as cisplatin are widely used in combination chemotherapy for non-small cell lung cancer (NSCLC) owing to their high clinical response rate; however, acquired resistance to cisplatin is eventually inevitable. Circular RNAs (circRNAs) are involved in the development of diverse types of cancers, but their connection to cisplatin-resistance in NSCLC has not been studied. In the present study, two cisplatin-resistant NSCLC cell lines (A549/DDP and PC9/DDP) were established by gradually increasing concentrations of cisplatin in the media. The resulting cell lines possessed high resistance to cisplatin and strong proliferation, migration, and colony formation abilities compared to the parental cells. Microarray analysis identified 19,161 circRNAs that were dysregulated in cisplatin-resistant cell lines (fold change abs>2), including 11,915 up-regulated and 7246 down-regulated circRNAs. The expression of the top five up-regulated and down-regulated circRNAs was validated using real-time quantitative polymerase chain reaction. A circRNA–micro RNA (miRNA) network of the top 20 dysregulated circRNAs and their predicted miRNAs was constructed using Cytoscape. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the host genes of the identified circRNAs were involved in the regulation of MAP kinase kinase kinase kinase activity, 6-phosphofructo-2-kinase activity, focal adhesion, ErbB signaling, and ECM-receptor interactions, which may contribute to cisplatin resistance in NSCLC. In summary, this is the first report on circRNA profiling in cisplatin-resistant NSCLC cells and it provides new potential targets for the reversal of cisplatin resistance in NSCLC.

中文翻译：

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综合分析耐顺铂非小细胞肺癌细胞系中环状RNA表达谱。

铂基药物（例如顺铂）因其高临床反应率而被广泛用于非小细胞肺癌（NSCLC）的联合化疗中。但是，最终获得的对顺铂耐药性是不可避免的。环状RNA（circRNA）参与了多种类型的癌症的发展，但尚未研究它们与NSCLC中顺铂耐药性的关系。在本研究中，通过逐渐增加培养基中顺铂的浓度，建立了两种耐顺铂的NSCLC细胞系（A549 / DDP和PC9 / DDP）。与亲代细胞相比，所得细胞系对顺铂具有很高的抵抗力，并且具有较强的增殖，迁移和集落形成能力。微阵列分析确定了19,161个circRNA在顺铂耐药细胞系中失调（倍数变化Abs> 2），包括11,915个上调和7246个下调的circRNA。使用实时定量聚合酶链反应验证了前五个上调和下调的circRNA的表达。使用Cytoscape构建了前20个失调的circRNA及其预测的miRNA的circRNA-micro RNA（miRNA）网络。基因本体论和《京都议定书》的基因和基因组百科全书通路分析表明，已鉴定的circRNA的宿主基因参与了MAP激酶激酶激酶激酶活性，6-磷酸果糖-2-激酶活性，粘着斑，ErbB信号传导和ECM的调控-受体相互作用，可能导致NSCLC的顺铂耐药性。综上所述，