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Heparanase-1 is upregulated by hepatitis C virus and favors its replication

  • Author Footnotes
    † Joint first authors.
    Christophe Gallard
    Footnotes
    † Joint first authors.
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Author Footnotes
    † Joint first authors.
    Nadjet Lebsir
    Footnotes
    † Joint first authors.
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Hira Khursheed
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Emma Reungoat
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Marie-Laure Plissonnier
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    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Jennifer Bré
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Maud Michelet
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Yasmina Chouik
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France

    Hospices Civils de Lyon, Lyon, France
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  • Fabien Zoulim
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France

    Hospices Civils de Lyon, Lyon, France
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  • Eve-Isabelle Pécheur
    Correspondence
    Tel. 0033478782806
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    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Author Footnotes
    § Joint senior authors.
    Birke Bartosch
    Footnotes
    § Joint senior authors.
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    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Author Footnotes
    § Joint senior authors.
    Boyan Grigorov
    Correspondence
    Corresponding authors. Address: Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Tel.: 0033472681963, fax: 0033472681971
    Footnotes
    § Joint senior authors.
    Affiliations
    Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
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  • Author Footnotes
    † Joint first authors.
    § Joint senior authors.
Published:January 24, 2022DOI:https://doi.org/10.1016/j.jhep.2022.01.008

      Highlights

      • Heparanase-1 (HPSE) is upregulated by HCV in an NF-κB-dependent manner.
      • HPSE favors HCV replication cycle at the virus release step.
      • HCV release is dependent on the tetraspanin CD63.
      • High HPSE levels may favor pathologic liver alterations.

      Background & Aims

      Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE).

      Methods

      HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection.

      Results

      HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation.

      Conclusions

      We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM.

      Lay summary

      Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM.

      Graphical abstract

      Keywords

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