TY - JOUR
T1 - RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage
AU - McClendon, A. Kathleen
AU - Dean, Jeffry L.
AU - Ertel, Adam
AU - Fu, Zhiyan
AU - Rivadeneira, Dayana B.
AU - Reed, Christopher A.
AU - Bourgo, Ryan J.
AU - Witkiewicz, Agnieszka
AU - Addya, Sankar
AU - Mayhew, Christopher N.
AU - Grimes, H. Leighton
AU - Fortina, Paolo
AU - Knudsen, Erik S.
N1 - Funding Information:
Funding Supported by National Institutes of Health grant 5R01CA127387 .
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - DEN
KW - Genetics
KW - Liver Cancer
KW - Mouse Model
KW - Tumor Environment
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U2 - 10.1053/j.gastro.2011.06.046
DO - 10.1053/j.gastro.2011.06.046
M3 - Article
C2 - 21704587
AN - SCOPUS:80053588225
SN - 0016-5085
VL - 141
SP - 1439
EP - 1450
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -