Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
Oncol Rep. 2019 Apr;41(4):2209-2225. doi: 10.3892/or.2019.7028. Epub 2019 Feb 21.
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 <0.05 and an absolute log value of fold-change >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.
本研究旨在通过构建调控环状 RNA（circRNA）-微小 RNA（miRNA）-信使 RNA（mRNA）网络，解析宫颈癌的发病机制并寻找新的生物标志物。采用调整后的 P 值 <0.05 和倍数变化的绝对对数值 >1，从 GSE30656 和癌症基因组图谱（TCGA）中获得了 16 个 miRNA 和 156 个 miRNA，从 GSE63514 中获得了 5321 个 mRNA，从 TCGA 中获得了 4076 个宫颈鳞状细胞癌和宫颈内膜腺癌的 mRNA，从 GSE102686 中获得了 75 个 circRNA。通过 RNAhybrid、Venn 和 UpSetR 图，获得了 12 个 circRNA-miRNA 对和 266 个 miRNA-mRNA 对。将这些对组合在一起，构建了一个包含 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评分 >5 和 >5 个节点构建蛋白质-蛋白质相互作用网络，鉴定出 7 个 hubgenes（RRM2、CEP55、CHEK1、KIF23、RACGAP1、ATAD2 和 KIF11）。通过将 7 个 hubgenes 映射到初步的 circRNA-miRNA-mRNA 网络中，构建了一个包含 5 个 circRNA（hsa_circRNA_000596、hsa_circRNA_104315、hsa_circRNA_400068、hsa_circRNA_101958 和 hsa_circRNA_103519）、2 个 miRNA（hsa-miR-15b 和 hsa-miR-106b）和 7 个 mRNA（RRM2、CEP55、CHEK1、KIF23、RACGAP1、ATAD2 和 KIF11）的 circRNA-miRNA-hubgenes 网络。在子网络中鉴定出 22 个 circRNA-miRNA-mRNA 调控轴。通过使用 Gene Expression Profiling Interactive Analysis 工具分析 7 个 hubgenes 的整体生存情况，发现 RRM2 的高表达与整体生存率显著降低相关。PharmGkb 分析确定了 RRM2 的 rs5030743 和 rs1130609 单核苷酸多态性（SNP），可以用克拉屈滨和阿糖胞苷治疗。RRM2 还参与了吉西他滨通路。5 个 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类似的效果，通过针对 rs5030743 和 rs1130609 或其他类似的 SNP 靶向 RRM2，可能成为治疗宫颈癌的可选化疗药物。然而，具体的作用机制还需要进一步研究来证实。
