Abstract
BACKGROUND: Numerous studies have shown circular RNA (circRNA) dysregulation is associated with the pathogenesis of cervical cancer,particularly in individual carcinoma variants. The aim of this study is to investigate and contrastively analyze the expression pattern of circRNAs in cervical squamous carcinoma and adenocarcinoma mediated by human papillomavirus type 16 (HPV-16). METHODS: The expression of circRNAs in cervical squamous carcinoma (SCC), adenocarcinoma (ADC) and adenosquamous carcinoma (ASC) tissues, together with the adjacent normal tissues (ANT), was profiled by high-throughput RNA sequencing (RNA-seq). Bioinformatics analysis and quantitative real time polymerase chain reaction (qRT-PCR) validation of the sequencing data were performed. A network of circRNA-miRNA (microRNA)-mRNA was then constructed according to predicted targets and function of candidate circRNAs. RESULTS: A total of 11,685 annotated circRNAs were identified in six cervical samples. There were 42 up-regulated and 98 down-regulated circRNAs. 215 circRNAs were up-regulated in SCC but down-regulated circRNAs in ADC, while 50 circRNAs displayed the opposite trend. Function enrichment analysis based on different expressions of circRNAs found that the most enriched pathway in all the three pathologic variants of cervical cancer was the "ubiquitin mediated proteolysis" pathway. Eight key candidate circRNAs derived from this pathway were further validated, and we noticed that several target miRNAs of candidate circRNAs could target the source genes. Based on this we constructed a related competing endogenous RNA (ceRNA) network. CONCLUSION: Through a comprehensive interpretation of differentially expressed circRNAs in different pathologic variants of cervical cancer, this study provides new insights into the process of tumor differentiation mediated by HPV. Our results may help to complement the molecular typing and stem cell theory of cervical cancer.