Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma

Hepatology. 2008 Feb;47(2):493-502. doi: 10.1002/hep.22027.

Abstract

Gankyrin (also known as PSMD10) is a liver oncoprotein that interacts with multiple proteins including MDM2 and accelerates degradation of the tumor suppressors p53 and Rb. We produced a monoclonal anti-gankyrin antibody and immunohistochemically assessed the clinicopathological significance of gankyrin overexpression in 43 specimens of human hepatocellular carcinoma (HCC). Specific cytoplasmic staining for gankyrin was observed in 62.8% (27/43) of HCCs, which was significantly associated with low TNM stage (P = 0.004), no capsular invasion (P = 0.018), no portal venous invasion (P = 0.008), and no intrahepatic metastasis (P = 0.012). The cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than that with gankyrin-negative HCC (P = 0.037). p53 and MDM2 were positively stained by antibodies in 30.2% and 23.3%, respectively, of HCCs, but neither was inversely associated with gankyrin expression. In the Huh-7 human HCC cell line, overexpression of gankyrin up-regulated expression of insulin-like growth factor binding protein 5 (IGFBP-5), whereas suppression of gankyrin expression by siRNA down-regulated it. Supression of IGFBP-5 expression inhibited proliferation of Huh-7 cells as well as U-2 OS osteosarcoma cells. In HCC specimens, positive staining for IGFBP-5 was observed by immunohistochemistry in 41.9% (18/43), and the level of expression was significantly correlated with that of gankyrin (rho = 0.629, P < 0.001).

Conclusion: These results suggest that gankyrin plays an oncogenic role(s) mainly at the early stages of human hepatocarcinogenesis, and that IGFBP-5 inducible by gankyrin overexpression may be involved in it.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 / genetics*
  • Liver Neoplasms / pathology*
  • Lymph Nodes / pathology
  • Mice
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Neoplasm Staging
  • Osteosarcoma
  • Plasmids
  • Proteasome Endopeptidase Complex / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Transfection

Substances

  • Insulin-Like Growth Factor Binding Protein 5
  • PSMD10 protein, human
  • Proto-Oncogene Proteins
  • Proteasome Endopeptidase Complex