Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2018; 24(1): 23-34
Published online Jan 7, 2018. doi: 10.3748/wjg.v24.i1.23
Construction of an oesophageal cancer-specific ceRNA network based on miRNA, lncRNA, and mRNA expression data
Wen-Hua Xue, Zhi-Rui Fan, Li-Feng Li, Jing-Li Lu, Bing-Jun Ma, Quan-Cheng Kan, Jie Zhao
Wen-Hua Xue, Jing-Li Lu, Bing-Jun Ma, Quan-Cheng Kan, Jie Zhao, Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Zhi-Rui Fan, Li-Feng Li, Cancer Centre, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Author contributions: Kan QC and Zhao J designed and coordinated the research; Xue WH drafted the manuscript; Fan ZR, Li LF, and Lu JL analysed the data; Ma BJ provided substantial contributions to conception of the manuscript, helped draft the article, and made critical revisions related to important intellectual content of the manuscript.
Supported by the National Natural Science Foundation of China, No. 31670895 and No. 71673254.
Institutional review board statement: The study was approved by the Institutional Ethics Review Board of Zhengzhou University, Zhengzhou, China.
Conflict-of-interest statement: The authors declare no conflicts of interest in the present study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Correspondence to: Jie Zhao, PhD, Professor, Department of Pharmacy, Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe Road, Zhengzhou 450052, Henan Province, China.
Telephone: +86-371-66913007 Fax: +86-371-66913335
Received: September 13, 2017
Peer-review started: September 13, 2017
First decision: October 24, 2017
Revised: November 7, 2017
Accepted: November 27, 2017
Article in press: November 27, 2017
Published online: January 7, 2018
Research background

Oesophageal squamous cell carcinoma (ESCC) is one of the most prevalent forms of oesophageal cancer, and its development is closely related to the abnormal expression of not only protein-encoding mRNAs, but also non-coding RNAs. Competitive endogenous RNAs (ceRNAs) regulatory networks include mRNAs, miRNAs, lncRNAs, and circular RNAs, which participate in the cancer pathogenesis by regulating each other’s expression. However, their function has not been clarified in ESCC. Therefore, construction of a ceRNA network for ESCC may help to study the biological mechanisms of this malignancy.

Research motivation

It is necessary to explore the CeRNA cross-talk across multiple cancer types. These issues have been addressed by TCGA, which provides large data sets enabling us with an unprecedented opportunity to synthetically explore the ceRNA network for various cancers. These findings led us to construct an oesophageal cancer-specific ceRNA network. The present study found that there were mRNAs, miRNAs, and lncRNAs in the ceRNA regulatory network, which might play a critical role in ESCC, and the abnormality in ceRNA regulatory networks would lead to the initiation and progression of ESCC.

Research objectives

Clustering analysis, mRNA GO analysis, mRNA pathway analysis, and protein regulation network analysis in oesophageal squamous cell carcinoma were conducted to construct a ceRNA network. These confirmed results suggested that the biological mechanisms in the development of ESCC may be indeed associated with the ceRNA network. Importantly, a simple framework was proposed in this study for constructing ceRNA networks in various biological processes including the study on ESCC.

Research methods

The expression data of miRNAs and mRNAs in 101 patients with esophageal cancer were obtained from the National Center for Biotechnology Information Gene Expression (NCBI). The expression profiles of 170 matched miRNAs and mRNAs in esophageal cancer patients were also obtained from TCGA (The Cancer Genome Atlas). The KEGG pathway and GO Term biological processes were identified with DAVID. The results were drawn with Cytoscape software, and were topologically analysed by Cytoscape’s network analyzer plugin. In addition, communities (dense clusters) in the network was found with Cycloscape, using the MCODE plug-in (the default). Based on the relationship between miRNAs, lncRNAs, and mRNAs, strands of stranded miRNAs have been established following transcriptional regulation of single nucleotide sequence-associated mRNA transcripts.

Research results

The results showed that the most highly enriched Gene Ontology path was ‘extracellular matrix organization’. The genes in ‘extracellular matrix organization’ path were MMP3, MMP10, LAMA3, MMP9, MMP13, COL11A1, BMP7, MMP12, LAMC2, COL27A1, ITGB4, PDGFRA, ADAMTS2, IBSP, COL10A1, COL7A1, MMP11, MFAP2, MMP1, and COL1A1. The advances in structural genomics may reveal the complete genomic sequence of thousands of organisms. The ceRNA network analysis indicated that the degree of has-miR-93-5p as an up-regulated gene was 14. All these results are meaningful for further development of treatments for oesophageal cancer. The overall survival was negatively associated with five mRNAs (STC2, SLC6A1, MMP12, EPCAM, and EPB41L4B), and it was positively related to the remaining mRNA (LAMC2). These mRNAs can be applied as promising specific biomarkers for ESCC. The significantly dysregulated mRNAs and miRNAs need to be validated in the future.

Research conclusions

A ceRNA network was identified in ESCC. The overall survival was negatively related to five mRNAs (STC2, SLC6A1, MMP12, EPCAM, and EPB41L4B). The ceRNA network has a significant effect in gene regulation and cancer development in ESCC. This study provides potential mechanisms for the development of oesophageal cancer and suggests new methods to modulate ceRNA networks for cancer treatment. CeRNA networks are implicated in the development of ESCC. A relationship between lncRNAs, miRNAs, and mRNAs in oesophageal squamous cell carcinoma was constructed by bioinformatics analysis. Cytoscape software showed the miRNA-lncRNA-mRNA interaction network and the Cytoscape network analyzer plug-in was used for topology analysis. In addition, the communities (dense clusters) in the network were found with the MCODE plug-in (with the default parameters). The bioinformatics analysis was performed on the co-expression of lncRNAs, miRNA, and mRNAs. The results showed that the most highly enriched GO path was ‘extracellular matrix organization’, which was associated with ESCC. By examining the ceRNA network, the node degrees were observed to follow a power law distribution. The expression of hsa-miR-196b-5p, has-miR-34c-5p, and has-miR-18a-3p was up-regulated. However, the levels of has-miR-30a-3p, has-miR-150-5p, and has-miR-133a-3p were down-regulated. The ceRNA network is associated with cancer progression. The understanding of ceRNA networks in ESCC may help uncover unexpected potential therapeutic targets that would be available in cancer sub-populations or across cancers.

Research perspectives

Understanding the ceRNA network is of significance in identifying potential therapeutic targets for ESCC. Our study focuses on the function and mechanism of ceRNAs in ESCC using publicly available genomic data.