Circ_MDM2_000139、Circ_ATF2_001418、Circ_CDC25C_002079 和 Circ_BIRC6_001271 参与 XAV939 在非小细胞肺癌中的功能。
Circ_MDM2_000139, Circ_ATF2_001418, Circ_CDC25C_002079, and Circ_BIRC6_001271 Are Involved in the Functions of XAV939 in Non-Small Cell Lung Cancer.
机构信息
Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China.
出版信息
Can Respir J. 2019 Nov 27;2019:9107806. doi: 10.1155/2019/9107806. eCollection 2019.
BACKGROUND
The small molecule inhibitor XAV939 could inhibit the proliferation and promote the apoptosis of non-small cell lung cancer () cells. This study was conducted to identify the key circular RNAs (circRNAs) and microRNAs (miRNAs) in XAV939-treated NSCLC cells.
METHODS
After grouping, the NCL-H1299 cells in the treatment group were treated by 10 M XAV939 for 12 h. RNA-sequencing was performed, and then the differentially expressed circRNAs (DE-circRNAs) were analyzed by the edgeR package. Using the clusterprofiler package, enrichment analysis for the hosting genes of the DE-circRNAs was performed. Using Cytoscape software, the miRNA-circRNA regulatory network was built for the disease-associated miRNAs and the DE-circRNAs. The DE-circRNAs that could translate into proteins were predicted using circBank database and IRESfinder tool. Finally, the transcription factor (TF)-circRNA regulatory network was built by Cytoscape software. In addition, A549 and HCC-827 cell treatment with XAV939 were used to verify the relative expression levels of key DE-circRNAs.
RESULTS
There were 106 DE-circRNAs (including 61 upregulated circRNAs and 45 downregulated circRNAs) between treatment and control groups. Enrichment analysis for the hosting genes of the DE-circRNAs showed that was enriched in the TNF signaling pathway. Disease association analysis indicated that 8 circRNAs (including circ_MDM2_000139, circ_ATF2_001418, circ_CDC25C_002079, and circ_BIRC6_001271) were correlated with NSCLC. In the miRNA-circRNA regulatory network, let-7 family members⟶circ_MDM2_000139, miR-16-5p/miR-134-5p⟶circ_ATF2_001418, miR-133b⟶circ_BIRC6_001271, and miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 regulatory pairs were involved. A total of 47 DE-circRNAs could translate into proteins. Additionally, circ_MDM2_000139 was targeted by the TF . The verification test showed that the relative expression levels of circ_MDM2_000139, circ_CDC25C_002079, circ_ATF2_001418, and circ_DICER1_000834 in A549 and HCC-827 cell treatment with XAV939 were downregulated comparing with the control.
CONCLUSIONS
Let-7 family members and targeting circ_MDM2_000139, miR-16-5p/miR-134-5p targeting circ_ATF2_001418, miR-133b targeting circ_BIRC6_001271, and miR-221-3p/miR-222-3p targeting circ_CDC25C_002079 might be related to the mechanism in the treatment of NSCLC by XAV939.
背景
小分子抑制剂 XAV939 能够抑制非小细胞肺癌（NSCLC）细胞的增殖并促进其凋亡。本研究旨在鉴定 XAV939 处理的 NSCLC 细胞中的关键环状 RNA（circRNA）和 microRNA（miRNA）。
方法
分组后，用 10 μM XAV939 处理实验组的 NCL-H1299 细胞 12 小时。进行 RNA 测序，然后使用 edgeR 包分析差异表达的 circRNAs（DE-circRNAs）。使用 clusterprofiler 包对 DE-circRNAs 的宿主基因进行富集分析。利用 Cytoscape 软件构建与疾病相关的 miRNA 和 DE-circRNAs 的 miRNA-circRNA 调控网络。使用 circBank 数据库和 IRESfinder 工具预测可翻译为蛋白质的 DE-circRNAs。最后，使用 Cytoscape 软件构建转录因子（TF）-circRNA 调控网络。此外，使用 XAV939 处理 A549 和 HCC-827 细胞以验证关键 DE-circRNAs 的相对表达水平。
结果
处理组和对照组之间有 106 个 DE-circRNAs（包括 61 个上调的 circRNAs 和 45 个下调的 circRNAs）。DE-circRNAs 的宿主基因富集分析表明，TNF 信号通路富集。疾病关联分析表明，8 个 circRNAs（包括 circ_MDM2_000139、circ_ATF2_001418、circ_CDC25C_002079 和 circ_BIRC6_001271）与 NSCLC 相关。在 miRNA-circRNA 调控网络中，let-7 家族成员⟶circ_MDM2_000139、miR-16-5p/miR-134-5p⟶circ_ATF2_001418、miR-133b⟶circ_BIRC6_001271 和 miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 调控对参与其中。共有 47 个 DE-circRNAs 可以翻译为蛋白质。此外，circ_MDM2_000139 受 TF 的靶向调控。验证实验表明，XAV939 处理的 A549 和 HCC-827 细胞中 circ_MDM2_000139、circ_CDC25C_002079、circ_ATF2_001418 和 circ_DICER1_000834 的相对表达水平均低于对照组。
结论
let-7 家族成员和 靶向 circ_MDM2_000139、miR-16-5p/miR-134-5p 靶向 circ_ATF2_001418、miR-133b 靶向 circ_BIRC6_001271 和 miR-221-3p/miR-222-3p 靶向 circ_CDC25C_002079 可能与 XAV939 治疗 NSCLC 的机制有关。
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