Reconstruction and analysis of circRNA-miRNA-mRNA network in the pathology of cervical cancer
Reconstruction and analysis of circRNA-miRNA-mRNA network in the pathology of cervical cancer
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DOI：
10.3892/or.2019.7028
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发表时间：
2019-04-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Yi, Yuexiong;Liu, Yanyan;Zhang, Wei
本研究旨在通过构建调控环（circular）RNA-micro（mi）RNA-mRNA网络，了解宫颈癌的发病机制，并为宫颈癌提供新的生物标志物。使用来自GSE 30656和癌症基因组图谱（TCGA）的1、16和156个miRNA的调整的P值，获得来自GSE 63514的5，321个mRNA、来自宫颈鳞状细胞癌和宫颈内腺癌（来自TCGA）的4，076个mRNA和来自GSE 102686的75个circRNA。利用RNAhybrid、Venn和UpSetR作图，共获得12对circRNA-miRNA对和266对miRNA-mRNA对。一旦这些对被组合，就构建了具有11个circRNA节点、4个miRNA节点、153个mRNA节点和203条边的circRNA-miRNA-mRNA网络。通过使用分子复合物检测得分>5和>5个节点构建蛋白质-蛋白质相互作用网络，鉴定了7个hubgenes（RRM 2、CEP 55、CHEK 1、KIF 23、RACGAP 1、ATAD 2和KIF 11）。通过将7个hubgenes定位到初步的circRNA-miRNA-mRNA网络中，构建了由5个circRNA组成的circRNA-miRNA-hubgenes网络，（hsa_circRNA_000596、hsa_circRNA_104315、hsa_circRNA_400068、hsa_circRNA_101958和hsa_circRNA_103519），2种mRNA构建了7种mRNA（hsa-miR-15 b和hsa-miR-106 b）和7种mRNA（RRM 2、CEP 55、CHEK 1、KIF 23、RACGAP 1、ATAD 2和KIF 11）。在该子网络中鉴定出22个circRNA-miRNA-mRNA调控轴。通过使用基因表达谱交互分析工具分析7个hubgenes的总生存期，证明RRM 2的较高表达与显著较差的总生存期相关。PharmGkb分析鉴定了RRM 2的rs 5030743和rs 1130609的单核苷酸多态性（SNP），其可以用克拉屈滨和阿糖胞苷治疗。RRM 2也被指示参与吉西他滨途径。5种circRNA（hsa_circRNA_000596、hsa_circRNA_104315、hsa_circRNA_400068、hsa_circRNA_101958和hsa_circRNA_103519）可能作为竞争性内源性RNA发挥作用，并在宫颈癌中发挥关键作用。此外，阿糖胞苷可能产生与吉西他滨相似的作用，并且可能是通过靶向rs 5030743和rs 1130609或其他类似SNP治疗宫颈癌的可选化疗药物。但具体作用机制有待进一步研究证实。
The present study was performed with the aim of understanding the mechanisms of pathogenesis and providing novel biomarkers for cervical cancer by constructing a regulatory circular (circ)RNA-micro (mi)RNA-mRNA network. Using an adjusted P-value of 1, 16 and 156 miRNAs from GSE30656 and The Cancer Genome Atlas (TCGA), 5,321 mRNAs from GSE63514, 4,076 mRNAs from cervical squamous cell carcinoma and endocervical adenocarcinoma (from TCGA) and 75 circRNAs from GSE102686 were obtained. Using RNAhybrid, Venn and UpSetR plot, 12 circRNA-miRNA pairs and 266 miRNA-mRNA pairs were obtained. Once these pairs were combined, a circRNA-miRNA-mRNA network with 11 circRNA nodes, 4 miRNA nodes, 153 mRNA nodes and 203 edges was constructed. By constructing the protein-protein interaction network using Molecular Complex Detection scores >5 and >5 nodes, 7 hubgenes (RRM2, CEP55, CHEK1, KIF23, RACGAP1, ATAD2 and KIF11) were identified. By mapping the 7 hubgenes into the preliminary circRNA-miRNA-mRNA network, a circRNA-miRNA-hubgenes network consisting of 5 circRNAs (hsa_circRNA_000596, hsa_circRNA_104315, hsa_circRNA_400068, hsa_circRNA_101958 and hsa_circRNA_103519), 2 mRNAs (hsa-miR-15b and hsa-miR-106b) and 7 mRNAs (RRM2, CEP55, CHEK1, KIF23, RACGAP1, ATAD2 and KIF11) was constructed. There were 22 circRNA-miRNA-mRNA regulatory axes identified in the subnetwork. By analyzing the overall survival for the 7 hubgenes using the Gene Expression Profiling Interactive Analysis tool, higher expression of RRM2 was demonstrated to be associated with a significantly poorer overall survival. PharmGkb analysis identified single nucleotide polymorphisms (SNPs) of rs5030743 and rs1130609 of RRM2, which can be treated with cladribine and cytarabine. RRM2 was also indicated to be involved in the gemcitabine pathway. The 5 circRNAs (hsa_circRNA_000596, hsa_circRNA_104315, hsa_circRNA_400068, hsa_circRNA_101958 and hsa_circRNA_103519) may function as competing endogenous RNAs and serve critical roles in cervical cancer. In addition, cytarabine may produce similar effects to gemcitabine and may be an optional chemotherapeutic drug for treating cervical cancer by targeting rs5030743 and rs1130609 or other similar SNPs. However, the specific mechanism of action should be confirmed by further study.