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


CONCLUSIONS
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.
Umemura
Atsushi
A
Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Itoh
Yoshito
Y
Itoh
Katsuhiko
K
Yamaguchi
Kanji
K
Nakajima
Tomoki
T
Higashitsuji
Hiroaki
H
Onoue
Hitoshi
H
Fukumoto
Manabu
M
Okanoue
Takeshi
T
Fujita
Jun
J
D000818:Animals; D001859:Bone Neoplasms; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics*; D008113:Liver Neoplasms / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D012516:Osteosarcoma; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014162:Transfection
D018975:Insulin-Like Growth Factor Binding Protein 5; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D046988:Proteasome Endopeptidase Complex