Candidate lncRNA–miRNA–mRNA network in predicting hepatocarcinogenesis with cirrhosis: an integrated bioinformatics analysis

  • Rui Zhang
  • Ying-yi Jiang
  • Kun Xiao
  • Xiao-quan Huang
  • Jian Wang
  • Shi-yao ChenEmail author
Original Article – Cancer Research



This study aimed to explore the potential competing endogenous RNA (ceRNA) network in forecasting HCC development in patients with cirrhosis through a comprehensive bioinformatic analysis.


Data mining from GEO and TCGA databases was employed to dig a spectrum of differentially expressed mRNA, lncRNA and miRNA profiles. Their expression was confirmed by RT-PCR in matched HCC cohorts (n = 6/group). The ceRNA network was constructed by co-expression analysis. Their reciprocal regulations and their roles in epithelial-to-mesenchymal transition (EMT) process were validated by gain- and loss-of-function experiments at the cellular level. Kaplan–Meier method was applied to reveal prognostic values.


By intersecting differentially expressed genes (DEGs) in GEO and TCGA data sets and Pearson correlation analysis, 20 mRNAs, 24 miRNAs and 41 lncRNAs were identified. Of these, FOXD2-AS1, BLVRA and CYTH2 were markedly upregulated in HCC tissues and HCC cells with high metastatic potential (MHCC97H) compared with their adjacent normal/cirrhotic tissues and L02 and MHCC97L cells. However, dysregulated miR-139-5p exhibited the opposite expression pattern. Using miRanda algorithms, FOXD2-AS1, BLVRA and CYTH2 showed potential binding sites for miR-139-5p. FOXD2-AS1 knockdown induced a marked increase in miR-139-5p and EMT inhibition. The loss of miR-139-5p led to an increase in BLVRA and CYTH2 expression and EMT process. Conversely, miR-139-5p overexpression suppressed BLVRA and CYTH expression and EMT process. FOXD2-AS1, miR-139-5p, BLVRA and CYTH2 highly correlated with prognosis in patients with HCC.


FOXD2-AS1/miR-139-5p/BLVRA or CYTH2 axis might be the underlying molecular mechanism that dissects HCC development caused by cirrhosis.


Bioinformatics Cirrhosis Hepatocellular carcinoma Differentially expressed genes Long non-coding RNAs miRNAs 



Competing endogenous RNA


Epithelial-to-mesenchymal transition


Differentially expressed genes


Hepatocellular carcinoma


Non-coding RNAs


Gene Expression Omnibus


The Cancer Genome Atlas


Gene Ontology


Kyoto Encyclopedia of Genes and Genomae


Author contributions

SYC conceived and designed the study. RZ, YYJ and KX performed the experiments. RZ, YYJ, KX and JW made statistical analysis. RZ and SYC analyzed the data and wrote the manuscript. RZ, XQH and SYC revised the manuscript.


This work was supported by the Innovation Fund of Science and Technology Commission of Shanghai Municipality (No. 15411950501, 15411950507 and 17140902700).

Compliance with ethical standards

Conflict of interest

The authors have declared that no competing interest exists.

Supplementary material

432_2019_3090_MOESM1_ESM.docx (74 kb)
Supplementary material 1 (DOCX 74 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology and Hepatology, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Center of Evidence-Based MedicineFudan UniversityShanghaiChina
  3. 3.Shanghai Institute of Liver DiseaseShanghaiChina
  4. 4.Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan HospitalFudan UniversityShanghaiChina
  5. 5.Endoscopy Center and Endoscopy Research Institute, Zhongshan HospitalFudan UniversityShanghaiChina

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