Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis.
Transcription factors with helix-loop-helix (HLH) motif play critical roles in controlling the expression of genes involved in lineage commitment, cell fate determination, proliferation, and tumorigenesis. To examine whether the newly identified HLH protein GCIP/CCNDBP1 modulates cell fate determination and plays a role in hepatocyte growth, proliferation, and hepatocarcinogenesis, we generated transgenic mice with human GCIP gene driven by a liver-specific albumin promoter. We demonstrated that in GCIP transgenic mice, the overall liver growth and regeneration occurred normally after liver injury induced by carbon tetrachloride (CCl4). In the diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis, we demonstrated that overexpression of GCIP in mouse liver suppressed DEN-induced hepatocarcinogenesis at an early stage of tumor development. The number of hepatic adenomas at 24 weeks was significantly lower or not detected in GCIP transgenic male mice compared to the control mice under the same treatment. Although GCIP has little inhibition on the number of hepatic tumors at later stages (40 weeks), hepatocellular tumors in GCIP transgenic mice are smaller and well-differentiated compared to the poorly differentiated tumors in wild-type mice. Furthermore, we demonstrate that GCIP functions as a transcriptional suppressor, regulates the expression of cyclin D1, and inhibits anchorage-independent cell growth and colony formation in HepG2 cells, suggesting a significant role of GCIP in tumor initiation and development.
Ma
W
W
Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
Xia
X
X
Stafford
L J
LJ
Yu
C
C
Wang
F
F
LeSage
G
G
Liu
M
M
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
C485815:CCNDBP1 protein, human; D002273:Carcinogens; D014157:Transcription Factors; D002251:Carbon Tetrachloride