RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage

A. Kathleen McClendon, Jeffry L. Dean, Adam Ertel, Zhiyan Fu, Dayana B. Rivadeneira, Christopher A. Reed, Ryan J. Bourgo, Agnieszka Witkiewicz, Sankar Addya, Christopher N. Mayhew, H. Leighton Grimes, Paolo Fortina, Erik S. Knudsen

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background & Aims: The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma. Methods: Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets. Results: Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma. Conclusions: The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors.

Original languageEnglish (US)
Pages (from-to)1439-1450
Number of pages12
JournalGastroenterology
Volume141
Issue number4
DOIs
StatePublished - Oct 2011

Keywords

  • DEN
  • Genetics
  • Liver Cancer
  • Mouse Model
  • Tumor Environment

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    McClendon, A. K., Dean, J. L., Ertel, A., Fu, Z., Rivadeneira, D. B., Reed, C. A., Bourgo, R. J., Witkiewicz, A., Addya, S., Mayhew, C. N., Grimes, H. L., Fortina, P., & Knudsen, E. S. (2011). RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage. Gastroenterology, 141(4), 1439-1450. https://doi.org/10.1053/j.gastro.2011.06.046