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

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.

Zhang SH ，Qian YM ，Liu AW ，Cai J ，Zhao XL ，Wei JJ ，Zhu MH ... -  《-》

Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence.

Ito Y ，Matsuura N ，Sakon M ，Miyoshi E ，Noda K ，Takeda T ，Umeshita K ，Nagano H ，Nakamori S ，Dono K ，Tsujimoto M ，Nakahara M ，Nakao K ，Taniguchi N ，Monden M ... -  《HEPATOLOGY》

CKS1B overexpression implicates clinical aggressiveness of hepatocellular carcinomas but not p27(Kip1) protein turnover: an independent prognosticator with potential p27 (Kip1)-independent oncogenic attributes?

Huang CW ，Lin CY ，Huang HY ，Liu HW ，Chen YJ ，Shih DF ，Chen HY ，Juan CC ，Ker CG ，Huang CY ，Li CF ，Shiue YL ... -  《-》

Nuclear expression of S-phase kinase-associated protein 2 predicts poor prognosis of hepatocellular carcinoma.

The S-phase kinase-associated protein 2 (Skp2), which ubiquitinates the cell cycle inhibitor p27(Kip1) and targets it for degradation, is commonly overexpressed in human cancers and is associated with poor prognosis in several cancers. The aim of this study was to investigate Skp2 expression and its clinicopathologic significance in surgically resected hepatocellular carcinomas. We collected 359 hepatocellular carcinoma samples and evaluated Skp2 protein expression in cytoplasmic and nuclear fractions by immunohistochemistry using a tissue microarray method. Among the 359 patients, nuclear expression of Skp2 was observed in 41 (10.38%), and cytoplasmic expression of Skp2 was observed in 195 (49.37%). Of the several clinicopathologic variables examined, high Edmonson-Steiner grade and early recurrence correlated with nuclear expression of Skp2 (p = 0.000 and 0.022, respectively). Cytoplasmic expression of Skp2 correlated negatively with microvascular and macrovascular invasion, tumor size, histologic grade, and overall survival. Multivariate analysis revealed that nuclear expression of Skp2 correlated with short disease-free survival. Our findings suggest that nuclear expression of Skp2 may be used as an independent predictor of poor prognosis for hepatocellular carcinoma, whereas cytoplasmic expression of Skp2 may indicate less aggressive disease.

Shin E ，Kim SH ，Jeong HY ，Jang JJ ，Lee K ... -  《-》

Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma.

Zhang SH ，Xu AM ，Chen XF ，Li DH ，Sun MP ，Wang YJ ... -  《-》