Abstract

BackgroundCircular RNA (circRNA) is a novel class of noncoding RNAs with functions in various pathophysiological activities. However, the expression profiles and functions of circRNAs in colorectal cancer (CRC) remain largely unknown.MethodsHigh-throughput RNA sequencing (RNA-seq) was performed to assess circRNA expression profiles in 4 paired CRC tissues, and significantly dysregulated circRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the potential functions of dysregulated circRNAs. Target miRNAs of circRNAs were predicted using miRanda software, and were further analyzed combining DIANA-miRPath v.3 platform (Reverse Search module) with KEGG pathways of COLORECTAL CANCER and MicroRNAs in cancer (Entry: map05210 and map05206). CircRNA-miRNA interaction networks were constructed using Cytoscape software. Expression levels of a significantly down-regulated circRNA, circDDX17 (hsa_circ_0002211), was detected by qRT-PCR in 60 paired CRC tissues. CircDDX17 was knockdown by siRNA, and the biological functions of circDDX17 were examined in CRC cell lines.ResultsTotally 448 differentially expressed circRNAs were identified, including 394 up-regulated and 54 down-regulated circRNAs. qRT-PCR validation confirmed the reliability of the RNA-Seq data. GO and KEGG analyses revealed that these dysregulated circRNAs were potentially implicated in CRC pathogenesis. Analyses by combining miRanda and miRPath softwares with KEGG pathways suggested that the miRNAs targeted by the top 10 dysregulated circRNAs were associated with the KEGG pathways of COLORECTAL CANCER and MicroRNAs in cancer, indicating that circRNA-miRNA interactions might play important functional roles in the initiation and progression of CRC. The results of qRT-PCR for circDDX17 in 60 paired CRC tissues showed that circDDX17 was significantly down-regulated in CRC tissues and associated with unfavorable clinicopathological parameters. In vitro experiments showed that silencing of circDDX17 promoted CRC cell proliferation, migration, invasion, and inhibited apoptosis.ConclusionsIn conclusion, we have identified numerous circRNAs that are dysregulated in CRC tissues compared with adjacent normal mucosa tissues. Bioinformatic analyses suggested that these dysregulated circRNAs might play important functional roles in CRC tumorigenesis. CircDDX17 functions as a tumor suppressor and could serve as a potential biomarker and a therapeutic target for CRC.

Highlights

  • Circular RNA is a novel class of noncoding RNAs with functions in various pathophysiological activities

  • Analyses by combining miRanda and miRPath softwares with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways suggested that the miRNAs targeted by the top 10 dysregulated circRNAs were associated with the KEGG pathways of COLORECTAL CANCER and MicroRNAs in cancer, indicating that circRNA-miRNA interactions might play important functional roles in the initiation and progression of colorectal cancer (CRC)

  • Expression profiles of circRNA in CRC A total of 21,458 circRNAs were detected by RNA-Seq in 4 pairs of CRC and adjacent normal mucosa tissues

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Summary

Introduction

Circular RNA (circRNA) is a novel class of noncoding RNAs with functions in various pathophysiological activities. The expression profiles and functions of circRNAs in colorectal cancer (CRC) remain largely unknown. Circular RNAs (circRNAs) represent a novel class of endogenous noncoding RNAs which do not have 5′ or 3′ ends but are covalently linked to form a closed circular structure [2]. CircRNAs differ from other RNAs because they are characterized by their covalently closed loop structures without 5′ caps and 3′ poly(A) tails [4]. This closed loop structure, which is called a “back-splicing” structure, is generated from the joining of an upstream 3′ splice acceptor to a downstream 5′ splice donor [5]. The exonic circRNAs are the most studied types of circRNAs

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