Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

Abstract

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 (CCl 4 ). 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 wildtype 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.

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

“…Liver injury causes liver regeneration primarily through hepatocyte division but if hepatocyte division is impaired, liver repair requires the recruitment of hepatic oval cells (Ma et al, 2006). Oval cells mainly express a-fetoprotein but not albumin, and can proliferate and differentiate into both hepatocytes and bile duct cells.…”

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…The TNAP-AID mouse model exhibits several characteristics of human HCC, in that the mice develop HCC spontaneously and the HCC tissue expresses a-fetoprotein and that it has the p53 gene mutations, some of which cause the same amino acid replacements as those seen in human tumours. Earlier HCC mouse models include mice with genetic modifications of Lkb1, Mdr2, Aox and Pten genes (Fan et al, 1998;Nakau et al, 2002;Horie et al, 2004;Katzenellenbogen et al, 2006), transgenic mice overexpressing c-myc, transforming growth factor-a, transforming growth factor-b1, HBx of hepatitis B virus and HCV core (Sandgren et al, 1989;Kim et al, 1991;Murakami et al, 1993;Koike et al, 1994Koike et al, , 2002Factor et al, 1997;Riehle et al, 2008) and chemical-or diet-induced HCC (Sell, 2001;Maeda et al, 2005;Ma et al, 2006;Sakurai et al, 2006). In contrast to these models, our TNAP-AID model is unique because it does not arbitrarily target specific oncogenes, tumour suppressors or stability genes.…”

Ribosomal phosphoprotein P0 interacts with GCIP and overexpression of P0 is associated with cellular proliferation in breast and liver carcinoma cells

“…Second, Sonnenberg-Riethmacher et al (2007) reported that lack of Maid (GCIP) promotes the occurrence of HCCs in older mice, suggesting the absence of GCIP can contribute to a higher tumor incidence in the liver. Third, Ma et al (2006) showed that overexpression of GCIP in mouse liver suppressed diethylnitrosamineinduced liver tumors in transgenic mice at an early stage of tumor development. Importantly, their studies suggest that GCIP might be a tumor suppressor protein.…”

“…Since GCIP could inhibit the expression of cyclin D1 protein in the cells (Ma et al, 2006), we also examined whether overexpression of P0 could enhance the expression of cyclin D1 protein in the cells. As shown in Figure 4, western blot analysis revealed that the expression level of cyclin D1 increased.…”