Dysregulation of fibrosis related genes in HCV induced liver disease
Copyright © 2018 Elsevier B.V. All rights reserved..
BACKGROUND: Liver fibrosis results from a wound healing response to chronic injury, which leads to excessive matrix deposition. Genome wide association studies have showen transcriptional dysregulation in mild and severe liver fibrosis. Recent studies suggested that genetic markers may be able to define the exact stage of liver fibrosis.
AIM: To define genes or genetic pathways that could serve as markers for staging or as therapeutic targets to halt progression of liver fibrosis.
METHODS: The study was performed on 105 treatment naïve HCV genotype 4 infected patients [F0-F2, n = 56; F3-F4, n = 49] and 16 healthy subjects. The study included PCR array on 84 fibrosis related genes followed by customization of a smaller array consisting of 11 genes that were designed on the bases of results obtained from the larger array. Genes that displayed significant dysregulation at mRNA levels were validated at protein levels.
RESULTS AND DISCUSSION: Two major pathways exhibited high dysregulation in early fibrosis as compared with controls or when compared with late fibrosis, these were the TGFβ - related pathway genes and Matrix - deposition associated genes. Hepatic stellate cell (HSC) activators i.e. TGFβ pathway genes [TGFβ1, 2 and 3, their receptors TGFβR1 and 2, signaling molecules SMAD genes and PDGF growth factors] were considerably over-expressed at transcriptional levels as early as F0, whereas expression of their inhibitor TGIF1 was simultaneously down regulated. Matrix proteins including collagen and MMPs were upregulated in early fibrosis whereas tissue inhibitors TIMPs 1 and 2 began over expression in late fibrosis. Expression at protein levels was concordant with RNA data excluding dysregulation at post transcriptional levels.
CONCLUSION: Since these 2 gene sets are closely interrelated regarding HSC activation and proliferation, we assume that the current findings suggest that they are favorable targets to further search for stage specific markers.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2018 |
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Erschienen: |
2018 |
Enthalten in: |
Zur Gesamtaufnahme - volume:664 |
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Enthalten in: |
Gene - 664(2018) vom: 20. Juli, Seite 58-69 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Dawood, Reham M [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 31.05.2018 Date Revised 31.05.2018 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.gene.2018.04.032 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM283323590 |
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100 | 1 | |a Dawood, Reham M |e verfasserin |4 aut | |
245 | 1 | 0 | |a Dysregulation of fibrosis related genes in HCV induced liver disease |
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520 | |a Copyright © 2018 Elsevier B.V. All rights reserved. | ||
520 | |a BACKGROUND: Liver fibrosis results from a wound healing response to chronic injury, which leads to excessive matrix deposition. Genome wide association studies have showen transcriptional dysregulation in mild and severe liver fibrosis. Recent studies suggested that genetic markers may be able to define the exact stage of liver fibrosis | ||
520 | |a AIM: To define genes or genetic pathways that could serve as markers for staging or as therapeutic targets to halt progression of liver fibrosis | ||
520 | |a METHODS: The study was performed on 105 treatment naïve HCV genotype 4 infected patients [F0-F2, n = 56; F3-F4, n = 49] and 16 healthy subjects. The study included PCR array on 84 fibrosis related genes followed by customization of a smaller array consisting of 11 genes that were designed on the bases of results obtained from the larger array. Genes that displayed significant dysregulation at mRNA levels were validated at protein levels | ||
520 | |a RESULTS AND DISCUSSION: Two major pathways exhibited high dysregulation in early fibrosis as compared with controls or when compared with late fibrosis, these were the TGFβ - related pathway genes and Matrix - deposition associated genes. Hepatic stellate cell (HSC) activators i.e. TGFβ pathway genes [TGFβ1, 2 and 3, their receptors TGFβR1 and 2, signaling molecules SMAD genes and PDGF growth factors] were considerably over-expressed at transcriptional levels as early as F0, whereas expression of their inhibitor TGIF1 was simultaneously down regulated. Matrix proteins including collagen and MMPs were upregulated in early fibrosis whereas tissue inhibitors TIMPs 1 and 2 began over expression in late fibrosis. Expression at protein levels was concordant with RNA data excluding dysregulation at post transcriptional levels | ||
520 | |a CONCLUSION: Since these 2 gene sets are closely interrelated regarding HSC activation and proliferation, we assume that the current findings suggest that they are favorable targets to further search for stage specific markers | ||
650 | 4 | |a Comparative Study | |
650 | 4 | |a Journal Article | |
650 | 4 | |a Fibrosis | |
650 | 4 | |a Gene expression | |
650 | 4 | |a HCV | |
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700 | 1 | |a Ibrahim, Marwa K |e verfasserin |4 aut | |
700 | 1 | |a Bader El Din, Noha G |e verfasserin |4 aut | |
700 | 1 | |a Barakat, Ahmed |e verfasserin |4 aut | |
700 | 1 | |a El-Wakeel, Khaled |e verfasserin |4 aut | |
700 | 1 | |a Alla, Mohamed Darwish Ahmed Abd |e verfasserin |4 aut | |
700 | 1 | |a Wu, George Y |e verfasserin |4 aut | |
700 | 1 | |a El Awady, Mostafa K |e verfasserin |4 aut | |
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