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

Atsushi Umemura, Yoshito Itoh, Katsuhiko Itoh, Kanji Yamaguchi, Tomoki Nakajima, Hiroaki Higashitsuji, Hitoshi Onoue, Manabu Fukumoto, Takeshi Okanoue, Jun Fujita

Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Hepatology (Baltimore, Md.) 2008 Feb

filter terms:

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 anti body 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). 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.

Citation

Atsushi Umemura, Yoshito Itoh, Katsuhiko Itoh, Kanji Yamaguchi, Tomoki Nakajima, Hiroaki Higashitsuji, Hitoshi Onoue, Manabu Fukumoto, Takeshi Okanoue, Jun Fujita. Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2008 Feb;47(2):493-502