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Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma

Authors Li H, Zhao X, Li C, Sheng C, Bai Z

Received 5 September 2018

Accepted for publication 23 November 2018

Published 17 January 2019 Volume 2019:11 Pages 877—897

DOI https://doi.org/10.2147/CMAR.S186561

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Antonella D'Anneo


Hongyan Li, Xiaonan Zhao, Chenghua Li, Chuanlun Sheng, Zhenzi Bai

Infectious Department, China-Japan Union Hospital, Jilin University, Changchun 130033, China

Background: There is evidence that abnormal expression of lncRNAs is associated with hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC). However, the mechanisms remain not fully elucidated. The study aimed to identify novel lncRNAs and explore their underlying mechanisms based on the ceRNA hypothesis.
Methods: The RNA and miRNA expression profiling in 20 tumor and matched adjacent tissues from HBV–HCC patients were retrieved from the Gene Expression Omnibus database under accession numbers GSE77509 and GSE76903, respectively. Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) were identified using the EdgeR package. Protein–protein interaction (PPI) network was constructed for DEGs followed by module analysis. The ceRNA network was constructed based on interaction relationships between miRNAs and mRNAs/lncRNAs. The functions of DEGs were predicted using DAVID and BinGO databases. The prognosis values (overall survival [OS] and recurrence-free survival [RFS]) of ceRNA network genes were determined using The Cancer Genome Atlas (TCGA) data with Cox regression analysis and Kaplan–Meier method.
Results: The present study screened 643 DELs, 83 DEMs, and 1,187 DEGs. PPI network analysis demonstrated that CDK1 and CCNE1 were hub genes and extracted in functionally related modules. E2F2, CDK1, and CCNE1 were significantly enriched into cell cycle pathway. FAM182B-miR-125b-5p-E2F2 and LINC00346-miR-10a-5p-CDK1/CCNE1 ceRNA axes were obtained by constructing the ceRNA network. Patients with high expressions of DELs and DEGs in the above ceRNA axes had poor OS, while patients with the high expression of DEMs possessed excellent OS. CDK1 was also an RFS-related biomarker, with its high expression predicting poor RFS. The upregulation of LINC00346 and CDK1 but the downregulation of miR-10a-5p in HCC was validated in other microarray datasets and TCGA database.
Conclusion: The LINC00346-miR-10a-5p-CDK1 axis may be an important mechanism for HBV-related HCC, and genes in this ceRNA axis may be potential prognostic biomarkers and therapeutic targets.

Keywords: hepatocellular carcinoma, hepatitis B virus, ceRNA, lncRNA, miRNA, prognosis, bioinformatics analysis, TCGA



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