RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis

Christopher N. Mayhew, Scott L. Carter, Sejal R. Fox, Charlene R. Sexton, Christopher A. Reed, Seetha V. Srinivasan, Xiangdong Liu, Kathryn Wikenheiser-Brokamp, Gregory P. Boivin, Ju Seog Lee, Bruce J. Aronow, Snorri S. Thorgeirsson, Erik S. Knudsen

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Background & Aims: The retinoblastoma (RB) tumor suppressor is functionally inactivated in most hepatocellular carcinomas (HCC), although the mechanisms by which RB suppresses liver tumorigenesis are poorly defined. We investigated the impact of RB loss on carcinogen-induced liver tumorigenesis. Methods: Mice harboring liver-specific RB ablation and normal littermates were exposed to the hepatocarcinogen diethylnitrosamine (DEN). The influence of RB loss on liver tumorigenesis was assessed by evaluating tumor multiplicity, proliferation, and genome integrity within tumors arising in RB-deficient and wild-type livers. In silico analyses were used to probe the association between gene expression signatures for RB loss and chromosomal instability and the ability of genes up-regulated by RB loss to predict the survival of human HCC patients. Results: RB deficiency significantly increased tumor multiplicity in livers exposed to DEN. Although hepatocytes in nontumor regions of DEN-exposed livers were quiescent regardless of RB status, tumors arising in RB-deficient livers were significantly more proliferative than those in normal livers and expressed high levels of RB/E2F target genes. Analysis of genes up-regulated by RB loss demonstrated significant overlap with a gene expression signature associated with chromosomal instability. Correspondingly, tumors arising in RB-deficient livers were significantly more likely to harbor hepatocytes exhibiting altered ploidy. Finally, gene expression analysis of human HCCs demonstrated that elevated expression of RB-regulated genes independently predicts poor survival. Conclusions: RB deletion in the mouse liver enhances DEN-induced tumorigenesis, associated with increased hepatocyte proliferation and compromised genome integrity. Evaluation of RB status may be a useful prognostic factor in human HCC.

Original languageEnglish (US)
Pages (from-to)976-984
Number of pages9
JournalGastroenterology
Volume133
Issue number3
DOIs
StatePublished - Sep 2007

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis'. Together they form a unique fingerprint.

  • Cite this

    Mayhew, C. N., Carter, S. L., Fox, S. R., Sexton, C. R., Reed, C. A., Srinivasan, S. V., Liu, X., Wikenheiser-Brokamp, K., Boivin, G. P., Lee, J. S., Aronow, B. J., Thorgeirsson, S. S., & Knudsen, E. S. (2007). RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis. Gastroenterology, 133(3), 976-984. https://doi.org/10.1053/j.gastro.2007.06.025