MiR-362-3p is downregulated by promoter methylation and independently predicts shorter OS of cervical squamous cell carcinoma

Abstract

The current study was undertaken to investigate the potential influence of methylation on miR-362-5p/3p expression and further analyzed their independent prognostic value in cervical adenocarcinoma (ADC) and squamous cell carcinoma (SCC) respectively. SiHa and CaSki cells were used as the in vitro cell model. In silico bioinformatic analysis was conducted via the combined use of the Cancer Genome Atlas-Cervical Cancer (TCGA-CESC), Starbase 3.0 and String 10.5. Results revealed that the downregulation of miR-362-5p/3p was accompanied by the infection of high-risk human papillomavirus (HR-HPV) and their expression was further decreased in HR-HPV cancer tissues. Demethylation could restore their expression. By performing Methylation-specific PCR (MSP) based on methylated or unmethylated specific primers, we confirmed that the proximal promoter region was methylated in both cell lines. Higher miR-362-3p expression might independently predict favorable overall survival (OS) in SCC patients (HR: 0.561, 95%CI: 0.354−0.889, p = 0.014), after adjustment of clinical stages, lymphovascular invasion and miR-362-5p expression. However, no prognostic value of miR-362-5p or miR-362-3p expression was observed in terms of OS in patients with ADC. Via bioinformatic analysis, we found that miR-362-3p might have an entirely different regulatory network in cervical ADC and SCC, which might help to explain the distinct prognostic value of miR-362-3p in these two histological subtypes. In summary, we infer that the methylation level of the proximal promoter region of pre-miR-362 would influence the expression of miR-362-5p/3p in cervical cancer. MiR-362-3p expression might be a specific prognostic biomarker in cervical SCC, but not in ADC.