title: Liver damage and senescence increases in patients developing hepatocellular carcinoma.
abstract: OBJECTIVE
  Most patients with a hepatocellular carcinoma (HCC) have an underlying chronic liver inflammation, which causes a continuous damage leading to liver cirrhosis and eventually HCC. However, only a minority of cirrhotic patients develop HCC. To assess a possible differential impact of liver inflammation in patients developing HCC versus patients remaining tumor-free, we designed a longitudinal study and analysed liver tissue of the same patients (n = 33) at two points in time: once when no HCC was present and once several years later when an HCC was present. As a control group, we followed cirrhotic patients (n = 37) remaining tumor-free over a similar time frame.
  
  
  METHODS
  We analysed cell damage and senescence of hepatocytes by measuring γ-H2AX positivity, p16INK4and p21WAF/Cip1expression, nuclear size, and telomere length.
  
  
  RESULTS
  γ-H2AX positivity, p16INK4and p21WAF/Cip1expression, in the first liver biopsy was similar in patients developing HCC later on and cirrhotic patients remaining tumor free. In contrast, γ-H2AX positivity, p16INK4and p21WAF/Cip1expression, was significantly higher in the second non-tumoral liver biopsy of HCC patients than in the control patients. Consequently, the individual increase in γ-H2AX positivity, p16INK4and p21WAF/Cip1expression, from the first biopsy to the second biopsy was significantly higher in patients developing HCC than in patients remaining tumor free. In addition, changes in nuclear size and telomere length revealed a more pronounced cell aging in patients developing HCC than in patients remaining tumor free.
  
  
  CONCLUSIONS
  Hepatocytes from patients developing HCC go through more pronounced cell damage and senescence in contrast to cirrhotic patients remaining tumor free.
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rey
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Quintavalle
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Burmeister
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Diego
authors.initials: D
authors.lastname: Calabrese
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schlageter
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland.
authors.forename: Gieri
authors.initials: G
authors.lastname: Cathomas
authors.affiliation: Institute of Pathology, Luzerner Kantonsspital, Lucerne, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.affiliation: Oral and Pharyngeal Cancer Branch, NIDCR-NIH, Bethesda, MD, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Matter
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D053145:Cell Nucleus Size; D016922:Cellular Senescence / Q000235:genetics; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000473:pathology*; D006657:Histones; D006801:Humans; D007249:Inflammation; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D059505:Telomere Homeostasis
chemical_list: C468783:H2AX protein, human; D006657:Histones
keywords: hepatocellular carcinoma; senescence; telomeres