Abstract
BackgroundCervical cancer is one of the most common cancers in women worldwide. Malignant tumors develop resistance mechanisms and are less sensitive to or do not respond to irradiation. With the development of high-throughput sequencing technologies, circular RNA (circRNA) has been identified in an increasing number of diseases, especially cancers. It has been reported that circRNA can compete with microRNAs (miRNAs) to change the stability or translation of target RNAs, thus regulating gene expression at the transcriptional level. However, the role of circRNAs in cervical cancer and the radioresistance mechanisms of HeLa cells are unknown. The objective of this study is to investigate the role of circRNAs in radioresistance in HeLa cells.MethodsHigh-throughput sequencing and bioinformatics analysis of irradiated and sham-irradiated HeLa cells. The reliability of high-throughput RNA sequencing was validated using quantitative real-time polymerase chain reaction. The most significant circRNA functions and pathways were selected by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA–miRNA–target gene interaction network was used to find circRNAs associated with radioresistance. Moreover, a protein–protein interaction network was constructed to identify radioresistance-related hub proteins.ResultsHigh-throughput sequencing allowed the identification of 16,893 circRNAs involved in the response of HeLa cells to radiation. Compared with the control group, there were 153 differentially expressed circRNAs, of which 76 were up-regulated and 77 were down-regulated. GO covered three domains: biological process (BP), cellular component (CC) and molecular function (MF). The terms assigned to the BP domain were peptidyl-tyrosine dephosphorylation and regulation of cell migration. The identified CC terms were cell–cell adherens junction, nucleoplasm and cytosol, and the identified MF terms were protein binding and protein tyrosine phosphatase activity. The top five KEGG pathways were MAPK signaling pathway, endocytosis, axon guidance, neurotrophin signaling pathway, and SNARE interactions in vesicular transport. The protein–protein interaction analysis indicated that 19 proteins might be hub proteins.ConclusionsCircRNAs may play a major role in the response to radiation. These findings may improve our understanding of the role of circRNAs in radioresistance in HeLa cells and allow the development of novel therapeutic approaches.
Highlights
Cervical cancer is one of the most common cancers in women worldwide and is responsible for the high mortality of female cancers (Du et al, 2012)
Recurrence and metastasis after radiotherapy remain a major problem in the treatment of locally-advanced cervical cancer (De Freitas, Gomes & Coimbra, 2015; Zhao et al, 2013)
CircRNAs are involved in many human diseases, including cancer (Burd et al, 2010; Bachmayr-Heyda et al, 2015)
Summary
Cervical cancer is one of the most common cancers in women worldwide and is responsible for the high mortality of female cancers (Du et al, 2012). Some studies have demonstrated that circRNAs play a major role in the biological function of a network of competing endogenous RNAs. Importantly, circRNAs may compete with micro RNAs (miRNAs) to change the stability and translation of target RNAs, regulating gene expression at the transcriptional level (Bachmayr-Heyda et al, 2015; Zhong et al, 2018; Ivanov et al, 2015; Qu et al, 2015). CircRNAs may compete with micro RNAs (miRNAs) to change the stability and translation of target RNAs, regulating gene expression at the transcriptional level (Bachmayr-Heyda et al, 2015; Zhong et al, 2018; Ivanov et al, 2015; Qu et al, 2015) Despite this significant progress, the expression profile, mechanism of action, and biological activity of circRNA have not been completely elucidated. The protein–protein interaction analysis indicated that 19 proteins might be hub proteins
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