DNA damage-induced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats

H. X. Yan, H. P. Wu, H. L. Zhang, C. Ashton, C. Tong, J. Wu, Q. J. Qian, H. Y. Wang, Q. L. Ying

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The tumor suppressor p53 has an important role in inducing cell-intrinsic responses to DNA damage, including cellular senescence or apoptosis, which act to thwart tumor development. It has been shown, however, that senescent or dying cells are capable of eliciting inflammatory responses, which can have pro-tumorigenic effects. Whether DNA damage-induced p53 activity can contribute to senescence- or apoptosis-associated pro-tumorigenic inflammation is unknown. Recently, we generated a p53 knock-out rat via homologous recombination in rat embryonic stem cells. Here we show that in a rat model of inflammation-associated hepatocarcinogenesis, heterozygous deficiency of p53 resulted in attenuated inflammatory responses and ameliorated hepatic cirrhosis and tumorigenesis. Chronic administration of hepatocarcinogenic compound, diethylnitrosamine, led to persistent DNA damage and sustained induction of p53 protein in the wild-type livers, and much less induction in p53 heterozygous livers. Sustained p53 activation subsequent to DNA damage was accompanied by apoptotic rather than senescent hepatic injury, which gave rise to the hepatic inflammatory responses. In contrast, the non-hepatocarcinogenic agent, carbon tetrachloride, failed to induce p53, and caused a similar degree of chronic hepatic inflammation and cirrhosis in wild type and p53 heterozygous rats. These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, especially in livers exposed to agents that inflict lasting mutagenic DNA damage.

Original languageEnglish (US)
Pages (from-to)4565-4571
Number of pages7
JournalOncogene
Volume32
Issue number38
DOIs
StatePublished - Sep 19 2013

Keywords

  • DNA damage
  • cirrhosis
  • hepatocellular carcinoma
  • inflammation
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Yan, H. X., Wu, H. P., Zhang, H. L., Ashton, C., Tong, C., Wu, J., Qian, Q. J., Wang, H. Y., & Ying, Q. L. (2013). DNA damage-induced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats. Oncogene, 32(38), 4565-4571. https://doi.org/10.1038/onc.2012.451