Identification of potential miRNA–mRNA regulatory network contributing to pathogenesis of HBV-related HCC

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Abstract

Background

Hepatitis B virus (HBV) is one of the major risk factors of hepatocellular carcinoma (HCC). Increasing evidence indicates that microRNA (miRNA)–mRNA axis is involved in HCC. However, a comprehensive miRNA–mRNA regulatory network in HBV-related HCC is still absent. This study aims to identify potential miRNA–mRNA regulatory pathways contributing to pathogenesis of HBV-related HCC.

Methods

Microarray GSE69580 was downloaded from Gene Expression Omnibus (GEO) database. GEO2R and ‘R-limma’ were used to conduct differential expression analysis. The common miRNAs appeared in the two analytic sets were screened as potential differentially expressed miRNAs (DE-miRNAs). The prognostic roles of screened DE-miRNAs in HCC were further evaluated using Kaplan–Meier plotter database. Target genes of DE-miRNAs were predicted by miRNet. Then, protein–protein interaction (PPI) networks were established for these targets via the STRING database, after which hub genes in the networks were identified by Cytoscape. Functional annotation and pathway enrichment analyses for the target genes were performed through DAVID database. Three enriched pathways related to HBV-related HCC were selected for further analysis and potential target genes commonly appeared in all three pathways were screened. Cytoscape was employed to construct miRNA-hub gene network. The expression and correlation of potential miRNAs and targets were further detected in clinical HBV-related HCC samples by qRT-PCR.

Results

7 upregulated and 9 downregulated DE-miRNAs were accessed. 5 of 7 upregulated DE-miRNAs and 5 of 7 downregulated DE-miRNAs indicated significant prognostic roles in HCC. 2312 and 1175 target genes were predicted for the upregulated and downregulated DE-miRNAs, respectively. TP53 was identified as the hub gene in the PPI networks. Pathway enrichment analysis suggested that these predicted targets were linked to hepatitis B, pathways in cancer, microRNAs in cancer and viral carcinogenesis. Further analysis of these pathways screened 20 and 16 target genes for upregulated and downregulated DE-miRNAs, respectively. By detecting the expression of 36 target genes, six candidate target genes were identified. Finally, a potential miRNA–mRNA regulatory network was established based on the results of qRT-PCR and expression correlation analysis.

Conclusions

In the study, potential miRNA–mRNA regulatory pathways were identified, exploring the underlying pathogenesis and effective therapy strategy of HBV-related HCC.

Electronic supplementary material

The online version of this article (10.1186/s12967-018-1761-7) contains supplementary material, which is available to authorized users.

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Most cited references 36

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An inducible long noncoding RNA amplifies DNA damage signaling

Adam Schmitt, Julia T. Garcia, Tiffany Hung … (2016)

Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding organismal DNA damage response. DNA damage activates transcription of DINO ( D amage Induced NO ncoding) via p53. DINO is required for p53-dependent gene expression, cell cycle arrest, and apoptosis in response to DNA damage, and DINO expression suffice to activate damage signaling and cell cycle arrest in the absence of DNA damage. DINO binds to and promotes p53 protein stabilization, mediating a p53 auto-amplification loop. Dino knockout or promoter inactivation in mice dampens p53 signaling and ameliorates acute radiation syndrome in vivo. Thus, inducible lncRNA can create a feedback loop with its cognate transcription factor to amplify cellular signaling networks.

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MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway

Changjun He, Xuesong Dong, Bo Zhai … (2015)

Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.

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Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis.

Nian-Zhang Zhang, Lei Kang, Yi Song … (2013)

MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

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Author and article information

Contributors

Weiyang Lou: 11718264@zju.edu.cn

Jingxing Liu: 526102864@qq.com

Bisha Ding: dingbisha@163.com

Danni Chen: chendanni90@126.com

Liang Xu: haixinlan@163.com

Jun Ding: ding1155665@zju.edu.cn

Donghai Jiang: jdh8499@zju.edu.cn

Lin Zhou: zhoulin99@zju.edu.cn

Shusen Zheng: shusenzheng@zju.edu.cn

Weimin Fan: fanw@zju.edu.cn

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 3 January 2019

Publication date PMC-release: 3 January 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 7

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Key Laboratory of Organ Transplantation, , Zhejiang University, ; 79 Qingchun Road, Hangzhou, 310003 Zhejiang Province China

[2 ]ISNI 0000 0004 1803 6319, GRID grid.452661.2, Key Laboratory of Organ Transplantation, ; Hangzhou, 310003 Zhejiang Province China

[3 ]ISNI 0000 0004 1769 3691, GRID grid.453135.5, Key Laboratory of Combined Multi-organ Transplantation, , Ministry of Public Health, ; Hangzhou, 310000 China

[4 ]Department of Intensive Care Unit, Changxing People’s Hospital of Zhejiang, Huzhou, 313100 Zhejiang Province China

[5 ]ISNI 0000 0001 2189 3475, GRID grid.259828.c, Department of Pathology and Laboratory Medicine, , Medical University of South Carolina, ; Charleston, SC 29425 USA

Article

Publisher ID: 1761

DOI: 10.1186/s12967-018-1761-7

PMC ID: 6317219

PubMed ID: 30602391

SO-VID: a4dcbb1c-f030-4812-8679-b063f4848e8b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 October 2018

Date accepted : 21 December 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81372462

Award ID: 81572987

Award Recipient : Weimin Fan

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: micrornas (mirnas),hepatocellular carcinoma (hcc),hepatitis b virus (hbv),bioinformatic analysis,kaplan–meier plotter (km-plotter)

Data availability:

ScienceOpen disciplines: Medicine

Keywords: micrornas (mirnas), hepatocellular carcinoma (hcc), hepatitis b virus (hbv), bioinformatic analysis, kaplan–meier plotter (km-plotter)

Identification of potential miRNA–mRNA regulatory network contributing to pathogenesis of HBV-related HCC

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Conclusions

Electronic supplementary material

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IEEE: COVID-19 related research

Most cited references 36

An inducible long noncoding RNA amplifies DNA damage signaling

MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway

Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis.

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