Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jun 26, 2021; 9(18): 4520-4541
Published online Jun 26, 2021. doi: 10.12998/wjcc.v9.i18.4520
Identification of the circRNA-miRNA-mRNA regulatory network and its prognostic effect in colorectal cancer
Teng-Fei Yin, Dong-Yan Zhao, Yuan-Chen Zhou, Qian-Qian Wang, Shu-Kun Yao
Teng-Fei Yin, Yuan-Chen Zhou, Qian-Qian Wang, Shu-Kun Yao, Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
Dong-Yan Zhao, Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Dong-Yan Zhao, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Author contributions: Yin TF conceived and designed the study, performed formal analysis and prepared the original draft; Zhao DY participated in data analysis and manuscript revision; Zhou YC and Wang QQ reviewed and edited the manuscript critically; Yao SK designed and supervised the study, revised the manuscript, and obtained the funding; all authors read and approved the final manuscript.
Supported by National Key Development Plan for Precision Medicine Research, No. 2017YFC0910002.
Institutional review board statement: This study was approved by the Ethics Committee of China-Japan Friendship Hospital, No. 2018-116-K85-1.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shu-Kun Yao, MD, PhD, Professor, Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, No. 2 Yinghua East Road, Chaoyang District, Beijing 100029, China. shukunyao@126.com
Received: December 11, 2020
Peer-review started: December 11, 2020
First decision: January 17, 2021
Revised: January 26, 2021
Accepted: February 26, 2021
Article in press: February 26, 2021
Published online: June 26, 2021
Abstract
BACKGROUND

The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored.

AIM

To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis.

METHODS

CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork.

RESULTS

We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs (CA2, ITLN1 and LRRC19) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC.

CONCLUSION

We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.

Keywords: CircRNA, miRNA, Network, Colorectal cancer, Prognosis, Biomarkers

Core Tip: The biological functions of circRNA and miRNA interactions and their potential as noninvasive biomarkers have not been well elucidated in colorectal cancer (CRC). In this study, we constructed a circRNA-miRNA-mRNA regulatory network with 19 circRNAs, 13 miRNAs and 28 mRNAs. GO and KEGG analyses indicated several signaling pathways probably involved in tumorigenesis. After being combined with survival analysis, a prognostic subnetwork was constructed including 5 circRNAs, 3 miRNAs and 3 mRNAs, which may represent novel diagnostic and prognostic candidate biomarkers, as well as therapeutic targets of CRC.