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Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer associated deaths worldwide. Independent studies have proposed altered DNA methylation pattern and aberrant microRNA (miRNA) levels leading to abnormal expression of different genes as important regulators of disease on...

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Autores principales: Zahid, Kashif Rafiq, Su, Mingyang, Khan, Abdur Rehman Raza, Han, Shiming, Deming, Gou, Raza, Umar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454777/
https://www.ncbi.nlm.nih.gov/pubmed/31007607
http://dx.doi.org/10.1186/s12935-019-0804-3
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author Zahid, Kashif Rafiq
Su, Mingyang
Khan, Abdur Rehman Raza
Han, Shiming
Deming, Gou
Raza, Umar
author_facet Zahid, Kashif Rafiq
Su, Mingyang
Khan, Abdur Rehman Raza
Han, Shiming
Deming, Gou
Raza, Umar
author_sort Zahid, Kashif Rafiq
collection PubMed
description BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer associated deaths worldwide. Independent studies have proposed altered DNA methylation pattern and aberrant microRNA (miRNA) levels leading to abnormal expression of different genes as important regulators of disease onset and progression in HCC. Here, using systems biology approaches, we aimed to integrate methylation, miRNA profiling and gene expression data into a regulatory methylation-miRNA–mRNA (meth-miRNA–mRNA) network to better understand the onset and progression of the disease. METHODS: Patients’ gene methylation, miRNA expression and gene expression data were retrieved from the NCBI GEO and TCGA databases. Differentially methylated genes, and differentially expressed miRNAs and genes were identified by comparing respective patients’ data using two tailed Student’s t-test. Functional annotation and pathway enrichment, miRNA–mRNA inverse pairing and gene set enrichment analyses (GSEA) were performed using DAVID, miRDIP v4.1 and GSEA tools respectively. meth-miRNA–mRNA network was constructed using Cytoscape v3.5.1. Kaplan–Meier survival analyses were performed using R script and significance was calculated by Log-rank (Mantel-Cox) test. RESULTS: We identified differentially expressed mRNAs, miRNAs, and differentially methylated genes in HCC as compared to normal adjacent tissues by analyzing gene expression, miRNA expression, and methylation profiling data of HCC patients and integrated top miRNAs along with their mRNA targets and their methylation profile into a regulatory meth-miRNA–mRNA network using systems biology approach. Pathway enrichment analyses of identified genes revealed suppressed metabolic pathways and hyperactive cell cycle signaling as key features of HCC onset and progression which we validated in 10 different HCC patients’ datasets. Next, we confirmed the inverse correlation between gene methylation and its expression, and between miRNA and its targets’ expression in various datasets. Furthermore, we validated the clinical significance of identified methylation, miRNA and mRNA signatures by checking their association with clinical features and survival of HCC patients. CONCLUSIONS: Overall, we suggest that simultaneous (1) reversal of hyper-methylation and/or oncogenic miRNA driven suppression of genes involved in metabolic pathways, and (2) induction of hyper-methylation and/or tumor suppressor miRNA driven suppression of genes involved in cell cycle signaling have potential of inhibiting disease aggressiveness, and predicting good survival in HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-019-0804-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-64547772019-04-19 Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression Zahid, Kashif Rafiq Su, Mingyang Khan, Abdur Rehman Raza Han, Shiming Deming, Gou Raza, Umar Cancer Cell Int Primary Research BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer associated deaths worldwide. Independent studies have proposed altered DNA methylation pattern and aberrant microRNA (miRNA) levels leading to abnormal expression of different genes as important regulators of disease onset and progression in HCC. Here, using systems biology approaches, we aimed to integrate methylation, miRNA profiling and gene expression data into a regulatory methylation-miRNA–mRNA (meth-miRNA–mRNA) network to better understand the onset and progression of the disease. METHODS: Patients’ gene methylation, miRNA expression and gene expression data were retrieved from the NCBI GEO and TCGA databases. Differentially methylated genes, and differentially expressed miRNAs and genes were identified by comparing respective patients’ data using two tailed Student’s t-test. Functional annotation and pathway enrichment, miRNA–mRNA inverse pairing and gene set enrichment analyses (GSEA) were performed using DAVID, miRDIP v4.1 and GSEA tools respectively. meth-miRNA–mRNA network was constructed using Cytoscape v3.5.1. Kaplan–Meier survival analyses were performed using R script and significance was calculated by Log-rank (Mantel-Cox) test. RESULTS: We identified differentially expressed mRNAs, miRNAs, and differentially methylated genes in HCC as compared to normal adjacent tissues by analyzing gene expression, miRNA expression, and methylation profiling data of HCC patients and integrated top miRNAs along with their mRNA targets and their methylation profile into a regulatory meth-miRNA–mRNA network using systems biology approach. Pathway enrichment analyses of identified genes revealed suppressed metabolic pathways and hyperactive cell cycle signaling as key features of HCC onset and progression which we validated in 10 different HCC patients’ datasets. Next, we confirmed the inverse correlation between gene methylation and its expression, and between miRNA and its targets’ expression in various datasets. Furthermore, we validated the clinical significance of identified methylation, miRNA and mRNA signatures by checking their association with clinical features and survival of HCC patients. CONCLUSIONS: Overall, we suggest that simultaneous (1) reversal of hyper-methylation and/or oncogenic miRNA driven suppression of genes involved in metabolic pathways, and (2) induction of hyper-methylation and/or tumor suppressor miRNA driven suppression of genes involved in cell cycle signaling have potential of inhibiting disease aggressiveness, and predicting good survival in HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-019-0804-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-08 /pmc/articles/PMC6454777/ /pubmed/31007607 http://dx.doi.org/10.1186/s12935-019-0804-3 Text en © The Author(s) 2019 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.
spellingShingle Primary Research
Zahid, Kashif Rafiq
Su, Mingyang
Khan, Abdur Rehman Raza
Han, Shiming
Deming, Gou
Raza, Umar
Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title_full Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title_fullStr Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title_full_unstemmed Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title_short Systems biology based meth-miRNA–mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
title_sort systems biology based meth-mirna–mrna regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454777/
https://www.ncbi.nlm.nih.gov/pubmed/31007607
http://dx.doi.org/10.1186/s12935-019-0804-3
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