Hepatitis C virus core protein induces hypoxia-inducible factor 1α-mediated vascular endothelial growth factor expression in Huh7.5.1 cells

Zhu, Chengliang; Liu, Xinghui; Wang, Shiqun; Yan, Xuesong; Tang, Zhaoming; Wu, Kailang; Li, Yan; Liu, Fang

doi:10.3892/mmr.2014.2039

Cited by 29 publications

(21 citation statements)

References 31 publications

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“…Besides the hypoxic microenvironment, HIF-1α and HIF-2α are also affected by many other factors, such as viral hepatitis infections, the glucose metabolism, proto-oncogenes, and mutated tumor suppressor genes (3)(4)(5)(6). It has been reported that both hepatitis B and C viruses can stabilize the HIF-1α protein and promote a pseudohypoxic state (1,3,7). HBV-encoded protein X (HBx) is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and genetic stability by directly or indirectly interacting with host factors (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Liu

Yang

et al. 2015

Oncology Reports

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A growing number of studies suggest that the hepatitis B virus X protein (HBx) enhances the protein stability of the hypoxia-inducible factor-1α (HIF-1α). However, the relationship between hepatitis B virus (HBV), HBx and hypoxia-inducible factor-2α (HIF-2α) has not yet been fully elucidated. Immunohistochemical analysis was employed to detect the expression of HIF-2α in normal liver, HBV-related chronic hepatitis, and HBV-related and non-HBV-related hepatocellular carcinoma (HCC) tissues. Quantitative real‑time PCR (qPCR) and western blotting were used to investigate the impact of HBV and HBx on the expression of HIF‑2α. Immunoprecipitation and immunofluorescence were applied to explore the underlying mechanisms. The HIF‑2α expression was found to be higher in HBV‑related chronic hepatitis tissues than in normal liver tissues. Furthermore, it was higher in HBV‑related HCC tissues and HBV‑integrated HepG2 cells than in the corresponding non‑HBV‑related HCC tissues and HepG2 cells. Both HBV and HBx enhanced the protein stability of HIF‑2α. HBx‑mediated upregulation of HIF‑2α resulted mainly from an inhibition of the degradation of HIF‑2α due to the binding of HBx to the von Hippel‑Lindau protein (pVHL). In addition, HBx upregulated the expression of HIF‑2α by activating the NF‑κB signaling pathway. Thus, the present study identified that HBV induces the HIF‑2α expression through its encoded protein HBx. This upregulates the HIF-2α expression by binding to the pVHL activating the NF-κB signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Liu

Yang

et al. 2015

Oncology Reports

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“…Our study demonstrated that, compared to healthy controls, our HCV patients show significantly higher serum levels of VEGF but serum aminotransferases did not correlate with VEGF in patients. Consequently, it was established that the enhanced regenerative capacity of hepatocytes rather than the hepatocyte damage per se is the cause of the increased serum VEGF [30,31]. The clinical utility of sVEG-FR1 as a pathogenic, diagnostic and/or prognostic marker in different medical conditions, including liver cirrhosis, either separately or accompanied with VEGF, was previously reported [39].…”

Section: Discussionmentioning

confidence: 98%

“…HCV viral-protein expression and infection severely impair mitochondrial oxidative phosphorylation leading to major reliance on nonoxidative glucose metabolism. This occurs through induction of HIF-1α and its dependent VEGF and glycolytic enzymes, in vitro and in vivo [30][31][32]. Interestingly, such hypoxic conditions and associated gene expression changes enhance HCV replication.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

et al. 2021

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Introduction: Hepatitis C virus (HCV) is the main cause of chronic liver disease, with calamitous complications. Its highest rate is recorded in Egypt. This study investigated whether oxidative stress, immunological chaos and cellular hypoxia are implicated in the pathophysiology of the disease. Material and methods: This cross-sectional study aimed to evaluate the changes in blood oxidative stress, cellular hypoxia/angiogenesis and cellular immunological biomarkers in hospital-diagnosed treatment-naïve HCV-infected Upper Egyptian chronic liver disease patients vs. healthy controls (n = 40). The consecutively included patients comprised 120 with normal serum enzymes (HCV-NE) and 130 with high serum enzymes (HCV-HE), along with 120 cirrhotic patients. Results: Oxidative stress biomarkers-malondialdehyde (MDA), total peroxides and oxidative stress index (OSI)-were significantly lower in controls vs. each of the patient groups. Cirrhotic patients presented the highest levels. However, total antioxidants (TAO) showed non-significant differences among the four groups. The cellular hypoxia/angiogenesis biomarkers-lactate, vascular endothelial cell growth factor (VEGF) and its soluble receptor 1 (sVEG-FR1)-vs. controls were massively increased in patient groups. VEGF was lowest while sVEGFR1 was highest among cirrhotic patients. Immunological biomarkers,-granulocyte/monocyte-colony stimulating factor (GM-CSF) and total immunoglobulin G (IgG)-were massively increased in patient groups vs. controls. GM-CSF was lowest in HCV-HE and IgG was highest in cirrhotic patients. sVEGFR1 correlated with the progression towards cirrhosis. Conclusions: Oxidative stress is implicated in the progress of HCV infection with marked induction of cellular hypoxia and dysfunctional angiogenesis, and a futile immunological reaction. sVEGFR1 level correlated with progression towards HCV-induced liver fibrosis.

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“…Notable was the upregulation of HIF-α (EPAS1 and HIF1A), which led to the up-regulation of growth factors (TGFB2, TGFB3, VEGFA, PDGFB) and glucose transporter SLC2A1/GLUT1. Previous studies have shown that the expression of HCV protein activates HIF-1 by normoxic stabilization of its α subunit (HIF-α), resulting in increased expression of HIFcontrolled genes, many of which are involved in tumor growth and metastasis, such as VEGF and TGF-β [53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

Wu¹

2015

Health Care: Current Reviews

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Background: Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono-and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups. Methods: Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono-and co-infection.

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Hepatitis C virus core protein induces hypoxia-inducible factor 1α-mediated vascular endothelial growth factor expression in Huh7.5.1 cells

Cited by 29 publications

References 31 publications

Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

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