Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma
Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma
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DOI：
10.1002/hep.22027
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发表时间：
2008-02-01
期刊：
影响因子：
13.5
通讯作者：
Fujita, Jun
中科院分区：
文献类型：
--
作者：
Umemura, Atsushi;Itoh, Yoshito;Fujita, Jun
Gankyrin（也称为PSMD 10）是一种肝脏癌蛋白，与包括MDM 2在内的多种蛋白相互作用，并加速肿瘤抑制因子p53和Rb的降解。我们制备了一种抗Gankyrin的单克隆抗体，并通过化学方法评估了43例人肝细胞癌（HCC）标本中Gankyrin过表达的临床病理意义。Gankyrin在62.8%（27/43）的HCC中表达，与TNM分期低（P = 0.004）、无包膜侵犯（P = 0.018）、无门静脉侵犯（P = 0.008）和无肝内转移（P = 0.012）相关。肝细胞癌中Gank 3阳性者的累积生存率显著高于Gank 3阴性者（P = 0.037）。p53和MDM 2抗体阳性率分别为30.2%和23.3%，但均与Gankyrin表达呈负相关。在Huh-7人肝癌细胞系中，gankyrin的过表达上调。siRNA抑制Gankyrin的表达可下调IGFBP-5的表达，抑制IGFBP-5的表达可抑制Huh-7和U-2 OS骨肉瘤细胞的增殖。IGFBP-5在HCC中的阳性表达率为41.9%（18/43），且与Gankyrin的表达水平呈显著正相关（rho = 0.629，P < 0.001）。结论：这些结果表明，Gankyrin主要在人类肝癌发生的早期阶段发挥致癌作用，并且Gankyrin过表达诱导的IGFBP-5可能参与其中。
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 tine, 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.