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.
Highlights
Cervical cancer is one of the most prevalent gynecological malignancies and the fourth most fatal cancer [1]
Because the dynamics of gene expression are characterized by a phasic pattern and cervical carcinogenesis is a gradual process [35], the role of circRNAs in the development of Cervical squamous cell carcinoma (CSCC) cannot be fully characterized
We provided comprehensive profiling of the transcriptome involving circRNA and mRNA from normal controls (NC) to high-grade squamous intraepithelial lesion (HSIL) and CSCC
Summary
Cervical cancer is one of the most prevalent gynecological malignancies and the fourth most fatal cancer [1]. Uterine cervix carcinogenesis is a step-by-step process that shows a continuum of neoplastic transitions from the persistence of high-risk human papillomavirus (HR-HPV, mostly HPV16) infection to low-grade squamous intraepithelial lesion (LSIL) to high-grade squamous intraepithelial lesion (HSIL) and to invasive cancer histologically [3]. It has been reported that almost half of HSILs will progress to invasive cancer [4, 5]. The molecular mechanism of cervical carcinogenesis is not completely understood, and previous studies of cervical precancerosis have been extremely limited. Exploration of the genetic changes and epigenetic modifications may reveal new clues to elucidate the molecular mechanisms of cervical carcinogenesis
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