Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease.
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.
Lechel
André
A
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany.
Holstege
Henne
H
Begus
Yvonne
Y
Schienke
Andrea
A
Kamino
Kenji
K
Lehmann
Ulrich
U
Kubicka
Stefan
S
Schirmacher
Peter
P
Jonkers
Jos
J
Rudolph
K Lenhard
KL
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
D004273:DNA, Neoplasm; D019098:Telomerase