Granulin-epithelin precursor and p53 in hepatocellular carcinoma

Abstract

Granulin-epithelin precursor (GEP) is a novel growth factor, and our earlier cDNA microarray study indicated that GEP was over-expressed in hepatocellular carcinoma (HCC) (Mol Biol Cell 2002).GEP was up-regulated in 72% HCC, associated with aggressivetumor features including large tumor, venous infiltration and earlyrecurrence, and functionally demonstrated to control growth, inva-sion and metastasis (Clin Cancer Res 2004). Somatic mutation andprotein accumulation of the p53 gene was common in HCC. We aimto investigate whether p53 protein and mutation status correlates withGEP expression in HCC. Statistical comparison of the p53 and GEPdata revealed an overall positive association between the two proteinexpression patterns (P < 0.001). On detailed analysis, p53 and GEPprotein expression association was highly significant only in HCCswith wild-type p53 (P = 0.001) but no association in HCC with p53mutation (P = 0.669). The GEP levels in hepatoma cell line HepG2,with wild-type p53 background, were modulated by transfectionexperiments. Over-expression of GEP protein resulted in increasedp53 protein level, and suppression of GEP protein resulted indecreased p53 protein level in HepG2 cells. In summary, we demon-strated that p53 wild-type protein nuclei accumulation is associated with GEP protein expression in human HCC specimens, and GEPmodulates p53 wild-type protein levels in vitro.