title: Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease.
abstract: OBJECTIVE
  During early stages of carcinogenesis most human epithelial cancers including hepatocellular carcinoma (HCC) have been observed to transit through a "crisis" stage characterized by telomere shortening, loss of p53 checkpoint function, and a sharp increase in aneuploidy. The function of telomerase during in vivo hepatocarcinogenesis has not been studied in this genetic context.
  
  
  METHODS
  Here we generated a mouse model in which HCC was induced by chronic organ damage (HBs-AG transgene) in the presence of telomere shortening and p53 deletion. Tumor development was analyzed in late-generation telomerase knockout mice (mTERC(-/-)) and littermates, genetically rescued for telomerase gene expression (mTERC(+/-)).
  
  
  RESULTS
  The formation of HCCs was strongly suppressed in mTERC(-/-) mice compared to mTERC(+/-) siblings correlating with reduced rates of tumor cell proliferation and elevated rates of tumor cell apoptosis. Although the prevalence of short telomeres was similar in chronically damaged liver of both cohorts, mTERC(-/-) HCC developed increased levels of DNA damage and aneuploidy compared to mTERC(+/-) HCC.
  
  
  CONCLUSIONS
  This study provides direct evidence that telomerase is a critical component for in vivo progression of p53 mutant HCC with short telomeres in the chronically damaged liver. In this molecular context, telomerase limits the accumulation of telomere dysfunction, the evolution of excessive aneuploidy, and the activation of p53-independent checkpoints suppressing hepatocarcinogenesis.
authors: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany.
authors: André
authors: A
authors: Lechel
authors: Henne
authors: H
authors: Holstege
authors: Yvonne
authors: Y
authors: Begus
authors: Andrea
authors: A
authors: Schienke
authors: Kenji
authors: K
authors: Kamino
authors: Ulrich
authors: U
authors: Lehmann
authors: Stefan
authors: S
authors: Kubicka
authors: Peter
authors: P
authors: Schirmacher
authors: Jos
authors: J
authors: Jonkers
authors: K Lenhard
authors: KL
authors: Rudolph
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005091:Exons; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D021141:Nucleic Acid Amplification Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D019098:Telomerase