Comprehensive Analysis of circRNA Expression Profiles During Cervical Carcinogenesis

Abstract

Circular RNAs (circRNAs) are regulatory molecules that participate in the occurrence, development and progression of tumors. To obtain a complete blueprint of cervical carcinogenesis, we analyzed the temporal transcriptomic landscapes of mRNAs and circRNAs. Microarrays were performed to identify the circRNA and mRNA expression profiles of cervical squamous cell carcinoma (CSCC) and high-grade squamous intraepithelial lesion (HSIL) patients compared with normal controls (NC). Short time-series expression miner (STEM) was utilized to characterize the time-course expression patterns of circRNAs and mRNAs from NC to HSIL and CSCC. A total of 3 circRNA profiles and 3 mRNA profiles with continuous upregulated patterns were identified and selected for further analysis. Furthermore, functional annotation showed that the mRNAs were associated with DNA repair and cell division. The protein-protein interaction (PPI) network analysis revealed that the ten highest-degree genes were considered to be hub genes. Subsequently, a competing endogenous RNA (ceRNA) network analysis and real-time PCR validation indicated that hsa_circ_0001955/hsa-miR-6719-3p/CDK1, hsa_circ_0001955/hsa-miR-1277-5p/NEDD4L and hsa_circ_0003954/hsa-miR-15a-3p/SYCP2 were highly correlated with cervical carcinogenesis. Silencing of hsa_circ_0003954 inhibited SiHa cell proliferation and perturb the cell cycle in vitro. This study provides insight into the molecular events regulating cervical carcinogenesis, identifies functional circRNAs in CSCC, and improves the understanding of the pathogenesis and molecular biomarkers of CSCC and HSIL.

Bioinformatics Screening of Potential Biomarkers from mRNA Expression Profiles to Discover Drug Targets and Agents for Cervical Cancer

“…On the other hand, we reviewed 52 published articles associated with CC infections that provided transcriptome-guided hub proteins (genomic biomarkers) for cross-validation of the proposed key genes and the candidate drug agents. There were 255 hub genes reported in those 52 articles, with 7 hub proteins (AURKA, PCNA, CCNB1, CDC45, MCM2, TOP2A, CDK1) appearing in at least 5 articles ( Table S2 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 23 , 24 , 25 , 26 , 27 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Five (AURKA, CCNB1, MCM2, TOP2A, and CDK1) of the seven reported hub proteins were found to be similar to our suggested seven KGs.…”

“…BRCA1 enhanced the sensitivity of cervical squamous cell carcinoma (CSCC) patients to cisplatin-based CCRT by up-regulating STAT1 to activate the JAK/STAT pathway [ 50 ]. CCNB1 played vital roles in the progression of CC through different signaling pathways [ 17 , 18 , 26 , 46 , 51 ]. CDK1 contributed to the occurrence and development of CSCC [ 18 , 23 , 25 , 26 , 27 , 40 , 41 , 44 , 46 ].…”

“…CCNB1 played vital roles in the progression of CC through different signaling pathways [ 17 , 18 , 26 , 46 , 51 ]. CDK1 contributed to the occurrence and development of CSCC [ 18 , 23 , 25 , 26 , 27 , 40 , 41 , 44 , 46 ]. MCM2 involved in the carcinogenesis of cervical cancer [ 16 , 19 , 20 , 21 , 23 , 27 , 42 ].…”

Metadata analysis to explore hub of the hub-genes highlighting their functions, pathways and regulators for cervical cancer diagnosis and therapies

“…TOP2A is considered a potential biomarker to improve the diagnosis of CC [ 12 , 13 , 20 , 24 , 32 , 40 , 42 , 44 , 55 , 56 ]. CDK1 may play a significant role in regulating the genetic network associated with cervical cancer occurrence, development, and metastasis [ 20 , 25 , 32 , 40 – 42 , 45 , 57 , 65 ]. PLK1 played a role in the occurrence and progression of CSCC [ 45 ].…”

“…To activate the JAK/STAT pathway BRCA1 increased the sensitivity of cervical squamous cell carcinoma (CSCC) patients to cisplatin-based CCRT with upregulated expression of STAT1 [ 54 ]. CCNB1 also enacted a key role in the development of CC under some signaling pathways [ 12 , 25 , 32 , 53 , 65 ]. Y. Liu et al reported that the progression of CC is activated by the expression of CCNA2 [ 41 ].…”