Reconstruction and analysis of circRNA‑miRNA‑mRNA network in the pathology of cervical cancer

Abstract

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.

Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis

“…Our results indicated that RRM2 is upregulated and significantly associated with poor prognosis in cervical cancer, and these results are in line with previous studies [18,19,36,40]. With 192 samples (29 normal, 30 low-grade dysplasia, 30 high-grade dysplasia and 103 invasive cancer tissue specimens) and SiHa cervical cancer cells, Su et al reported the expression of RRM2 in cancer tissues was increased when compared to high-grade dysplasia, low-grade dysplasia or normal cervical tissues [40].…”

“…In addition, our previous research has also shown that higher expression of RRM2 is associated with a significantly poorer overall survival [18]. However, relatively little is known about the role of RRM2 in cervical cancer and even less is known of the mechanisms responsible for its effects.…”

“…International Publisher adrenocortical cancer [8], lung cancer [9], nasopharyngeal cancer [10], gastric cancer [11] and neuroblastoma [12], as well as being a predictor of poor prognosis [13][14][15][16][17]. Our previous study had indicated that RRM2 plays a critical role in the diagnosis and treatment of cervical cancer [18]. In addition, upregulation of RRM2 was found to lead to promotion of angiogenesis, whereas its downregulation significantly increased apoptosis and promoted cell cycle arrest in cervical cancer [6,19].…”

<p>Circular RNA circ_0006282 Contributes to the Progression of Gastric Cancer by Sponging miR-155 to Upregulate the Expression of FBXO22</p>

“…Recent studies have shown that circRNAs can exert as a sponge on miRNAs to regulate the expression of downstream target genes of miRNAs and affect tumor occurrence and development. [18][19][20] MiR-155 is an important member of the microRNAs family, and due to its versatile nature, miR-155 has attracted extensive attention and extensive research. A large number of studies have shown that miR-155 has a wide range of functions, involving many biological processes such as developmental differentiation of hematopoietic cells, developmental differentiation of immune cells, inflammatory response, immune response, muscle development, and fat differentiation.…”

A Three-Gene Prognostic Signature Based on Circular RNA-Associated Competing Endogenous RNA Network for Patients with Lung Adenocarcinoma

“…DEcircRNAs with the target miRNAs. To obtain high-quality circRNAs acting as miRNA targets and distinguish those circRNAs acting as miRNA decoys, the circRNAs that had perfect nucleotide pairing between the 2nd and 8th positions of the 5' end of miRNA sequences were selected [17]. The miRNAs within circRNA-miRNA interactions were further screened by DEmiRNAs identi ed from TCGA.…”