Abstract

Recently, accumulating evidence has supported that circular RNA (circRNA) plays important roles in tumorigenesis by regulating gene expression at transcriptional and post-transcriptional levels. Expression of circRNAs can be epigenetically silenced by DNA methylation; however, the underlying regulatory mechanisms of circRNAs by DNA methylation remains largely unknown. We explored this regulation in hepatocellular carcinoma (HCC) using genome-wide DNA methylation and RNA sequencing data of the primary tumor and matched adjacent normal tissues from 20 HCC patients. Our pipeline identified 1012 upregulated and 747 downregulated circRNAs (collectively referred to as differentially expressed circRNAs, or DE circRNAs) from HCC RNA-seq data. Among them, 329 DE circRNAs covered differentially methylated sites (adjusted p-value < 0.05, |ΔM| > 0.5) in circRNAs’ interior and/or flanking regions. Interestingly, the corresponding parental genes of 46 upregulated and 31 downregulated circRNAs did not show significant expression change in the HCC tumor versus normal samples. Importantly, 34 of the 77 DE circRNAs (44.2%) had significant correlation with DNA methylation change in HCC (Spearman’s rank-order correlation, p-value < 0.05), suggesting that aberrant DNA methylation might regulate circular RNA expression in HCC. Our study revealed genome-wide differential circRNA expression in HCC. The significant correlation with DNA methylation change suggested that epigenetic regulation might act on both mRNA and circRNA expression. The specific regulation in HCC and general view in other cancer or disease requires further investigation.

Highlights

  • We developed in-house computational pipelines and characterized 12,097 differentially expressed (DE) mRNAs, 312 DE miRNAs, 1759 DE circRNAs, and 191,757 differentially methylated (DM) sites based on a published dataset in hepatocellular carcinoma (HCC)

  • To improve the analysis confidence of our study, we focused on the circRNA that could be identified in at least two samples, resulting in

  • By combining the circRNA expression, mRNA expression, and DNA methylation changes in our study, we found a total of 77 DE circRNAs (46 upregulated and 31 downregulated) had significant DM sites, while their parental genes had no differential expression in tumor versus normal samples

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Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies around the world [1]. Clinical investigation has shown that HCC is the sixth most common cancer and the fourth main cause of cancer mortality worldwide [2,3]. HCC patients are amenable to curative therapy. The available treatment approaches for HCC include resection, liver transplantation, image-guided tumor ablation, and systemic therapy [4]. The prognosis of HCC patients is still not satisfactory, owing to tumor recurrence and metastasis with high frequency [5]. There is a strong need to identify specific biomarkers for prognosis predication and new effective targets to design a powerful therapeutic approach

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