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Hypoxia Induces Pro-Fibrotic and Fibrosis Marker Genes in Hepatocellular Carcinoma Cells Independently of Inflammatory Stimulation and the NF-κΒ Pathway

Authors Triantafyllou EA, Mylonis I, Simos G, Paraskeva E

Received 24 October 2019

Accepted for publication 16 December 2019

Published 24 December 2019 Volume 2019:7 Pages 87—91

DOI https://doi.org/10.2147/HP.S235967

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Eleni-Anastasia Triantafyllou,1 Ilias Mylonis,2 George Simos,2 Efrosyni Paraskeva1

1Department of Physiology, Faculty of Medicine, University of Thessaly, Larissa, Greece; 2Department of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece

Correspondence: Efrosyni Paraskeva Tel +30-2410-685559
Fax +30-2410-685555
Email fparaskeva@med.uth.gr
George Simos
Faculty of Medicine, University of Thessaly, Panepistimiou 3, Larissa, Greece
Tel +30-2410-685723
Fax +30-2410-685555
Email simos@med.uth.gr

Abstract: Hypoxia and its key mediators hypoxia inducible Factors (HIFs) are implicated in the development of liver diseases of diverse etiologies, often in interplay with inflammatory mediators. We investigated the interplay between hypoxia and proinflammatory mediators in the development of liver fibrosis, using human hepatocellular carcinoma Huh7 cells as a model. Treatment of Huh7 with DMOG or under hypoxia, induced HIF-1α protein levels and the expression of genes for profibrotic (TGF-β1, PDGFC, PAI-1) and fibrosis (LOX, P4HA1, P4HB) markers. Knockdown of HIF-1α decreased the induction of PDGFC, LOX and P4HA1, showing the involvement of HIF-1 in their regulation. Interestingly, incubation of Huh7 cells under hypoxia did not cause activation of the NF-κΒ pathway. In contrast, inflammatory mediators such as tumor necrosis factor α (TNFα) and lipopolysaccharides (LPS) activated the NF-κΒ pathway, but failed to increase HIF-1α protein levels. Moreover, TNFα had a weaker effect than hypoxia on the induction or did not induce profibrotic and fibrosis markers, respectively, while LPS enhanced only the hypoxic induction of P4HB. In conclusion, the above findings suggest that hypoxia and HIF-1 play an important role in the development of fibrosis in hepatocellular carcinoma, which appears to be independent of the
activation of the NF-κΒ pathway.

Keywords: Huh7, HIF-1, fibrosis, NF-κΒ, TNFα, LPS


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