Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression

Paraskevi A. Farazi, Jonathan Glickman, James Horner, Ronald A. DePinho

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Hepatocellular carcinoma is among the most common and lethal cancers in humans. Hepatocellular carcinoma is commonly associated with physical or functional inactivation of the p53 tumor suppressor, high levels of chromosomal instability, and disease conditions causing chronic cycles of hepatocyte death and regeneration. Mounting evidence has implicated regeneration-induced telomere erosion as a potential mechanism fueling genome instability. In mouse models of hepatocellular carcinoma, telomere dysfunction has been shown to enhance initiation of hepatic neoplasias yet constrain full malignant progression of these neoplasms possibly due to activation of a p53-dependent checkpoint and/or intolerable levels of genomic instability. Here, in a hepatocellular carcinoma-prone model brought about through toxin-induced hepatocyte injury and regeneration, we sought to determine the cooperative interactions of germ line p53 mutation and telomere dysfunction [produced by telomerase reverse transcriptase (mTERT) gene knockout]. In the setting of intact telomeres, p53 mutation had no effect on hepatocarcinogenesis, whereas in the setting of telomere dysfunction, p53 mutation enabled advanced hepatocellular carcinoma disease. Notably, there was no evidence of deletion or mutation of the wild-type p53 allele in the late generation mTert -/-p53 +/- mice, suggesting that reduced levels of p53 potently enable hepatocellular carcinoma progression in the setting of telomere dysfunction. Thus, this study supports a model that, in the face of chronic liver damage, attenuated p53 function and telomere-induced chromosomal instability play critical and cooperative roles in the progression of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)4766-4773
Number of pages8
JournalCancer Research
Volume66
Issue number9
DOIs
StatePublished - May 1 2006

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Telomere
Liver Diseases
Hepatocellular Carcinoma
Mutation
Regeneration
Chromosomal Instability
Genomic Instability
Hepatocytes
Neoplasms
Gene Knockout Techniques
Germ-Line Mutation
Sequence Deletion
Telomerase
Liver
Alleles
Wounds and Injuries

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. / Farazi, Paraskevi A.; Glickman, Jonathan; Horner, James; DePinho, Ronald A.

In: Cancer Research, Vol. 66, No. 9, 01.05.2006, p. 4766-4773.

Research output: Contribution to journalArticle

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