title: Cause-specific telomere factors deregulation in hepatocellular carcinoma.
abstract: BACKGROUND
  Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.
  
  
  METHODS
  Here, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.
  
  
  RESULTS
  Alterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.
  
  
  CONCLUSIONS
  These results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.
authors.affiliation: UMR5239 Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, CNRS, Pierre Bénite, France. eric.wattel@ens-lyon.fr.
authors.forename: Manale
authors.initials: M
authors.lastname: El Idrissi
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005260:Female; D016174:Hepacivirus / Q000302:isolation & purification; D006509:Hepatitis B / Q000473:pathology; D006515:Hepatitis B virus / Q000302:isolation & purification; D006526:Hepatitis C / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism* / Q000473:pathology
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase
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