TY - JOUR
T1 - RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis
AU - Mayhew, Christopher N.
AU - Carter, Scott L.
AU - Fox, Sejal R.
AU - Sexton, Charlene R.
AU - Reed, Christopher A.
AU - Srinivasan, Seetha V.
AU - Liu, Xiangdong
AU - Wikenheiser-Brokamp, Kathryn
AU - Boivin, Gregory P.
AU - Lee, Ju Seog
AU - Aronow, Bruce J.
AU - Thorgeirsson, Snorri S.
AU - Knudsen, Erik S.
N1 - Funding Information:
Supported by NCI grants CA106471 (to E.S.K.) and T32 CA 59268 (to C.N.M.); NIH grant U01 ES11038-02 (to G.P.B.); and the Ministry of Science and Technology, Korea (to J.S.L.).
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34548483149&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548483149&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.06.025
DO - 10.1053/j.gastro.2007.06.025
M3 - Article
C2 - 17854601
AN - SCOPUS:34548483149
SN - 0016-5085
VL - 133
SP - 976
EP - 984
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -