Clinicopathologic significance and function of S-phase kinase-associated protein 2 overexpression in hepatocellular carcinoma☆☆☆

Summary 

The F-box protein S-phase kinase-associated protein 2 is frequently overexpressed in human cancers. Herein, we aimed to investigate the expression pattern, clinical significance, and biological function of S-phase kinase-associated protein 2 in hepatocellular carcinoma. Analysis by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry revealed that S-phase kinase-associated protein 2 was aberrantly overexpressed in hepatocellular carcinomas relative to adjacent nontumor liver tissues. This overexpression was significantly associated with advanced tumor stage, increased histologic grade, vascular invasion, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the endogenous S-phase kinase-associated protein 2 expression in 1 hepatocellular carcinoma cell line, Huh7, by RNA interference reduced cell proliferation, blocked the cell cycle at G1 phase, and increased apoptosis. S-phase kinase-associated protein 2 silencing resulted in a deregulation of multiple cell-cycle regulatory proteins in Huh7 cells, as detected by quantitative real-time polymerase chain reaction arrays. Furthermore, high S-phase kinase-associated protein 2 immunoreactivity was found to be significantly correlated with reduced expression of P27, P21, and cell-cycle checkpoint kinase 2, as well as with increased expression of transcription factors Dp-1, cyclin D2, and cyclin D1 in hepatocellular carcinoma tissues. These data demonstrate that S-phase kinase-associated protein 2 expression is closely linked to tumor progression and represents an independent predictor of poor prognosis in hepatocellular carcinoma. S-phase kinase-associated protein 2 is involved in hepatocellular carcinoma cell proliferation through regulating numerous genes involved in cell-cycle progression, thereby providing a potential therapeutic target for this malignancy.

Keywords: Hepatocellular carcinoma, SKP2, Prognosis, RNA interference, Cell cycle