title: HCMV activates the IL-6-JAK-STAT3 axis in HepG2 cells and primary human hepatocytes.
abstract: OBJECTIVE
  There has been increased interest in the possible role of human cytomegalovirus (HCMV) in carcinogenesis during the last decade. HCMV seroprevalence was enhanced in patients with hepatocellular carcinoma (HCC) but a possible relationship between HCC and HCMV infection remained to be assessed. The aim of this work was to investigate the pro-tumor influence of HCMV on primary human hepatocytes (PHH) and HepG2 cells.
  
  
  METHODS
  Following infection of PHH and HepG2 cells by two different strains of HCMV, we measured the production of IL-6 in culture supernatants by ELISA and the protein levels of STAT3, pSTAT3, JAK, cyclin D1, survivin, p53, p21, and Mdm2 by western Blotting in infected and uninfected cells. Cell proliferation and transformation were investigated using Ki67Ag expression measurement and soft-agar colony formation assay respectively.
  
  
  RESULTS
  Infection of HepG2 cells and PHH by HCMV resulted in the production of IL-6 and the subsequent activation of the IL-6R-JAK-STAT3 pathway. HCMV increased the expression of cyclin D1 and survivin. Cell proliferation was enhanced in HepG2 and PHH infected with HCMV, despite a paradoxical overexpression of p53 and p21. More importantly, we observed the formation of colonies in soft agar seeded with PHH infected with HCMV and when we challenged the HepG2 cultures to form tumorspheres, we found that the HCMV-infected cultures formed 2.5-fold more tumorspheres than uninfected cultures.
  
  
  CONCLUSIONS
  HCMV activated the IL-6-JAK-STAT3 pathway in PHH and HepG2 cells, favored cellular proliferation, induced PHH transformation and enhanced HepG2 tumorsphere formation. Our observations raise the possibility that HCMV infection might be involved in the genesis of hepatocellular carcinoma.
authors.affiliation: Department of Virology, University of Franche-Comté, EA 4266 Pathogens & Inflammation, SFR FED4234, CHU Besançon, Besançon, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Lepiller
authors.forename: Wasim
authors.initials: W
authors.lastname: Abbas
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Tripathy
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003587:Cytomegalovirus / Q000502:physiology*; D004789:Enzyme Activation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D053612:Janus Kinases
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