CKS1B Overexpression Implicates Clinical Aggressiveness of Hepatocellular Carcinomas but Not p27Kip1 Protein Turnover: an Independent Prognosticator with Potential p27Kip1-Independent Oncogenic Attributes?

Ching-Wen Huang, Ching-Yih Lin, Hsuan-Ying Huang, Hui-Wen Liu, Yi-Ju Chen, Deng-Fuh Shih, Hong-Yaw Chen, Chung-Chou Juan, Chen-Guo Ker, Chi-Ying F. Huang, Chien-Feng Li, Yow-Ling Shiue PhD
Translational Research and Biomarkers
Volume 17, Issue 3 / March , 2009

View full article HTML | View full article PDF | Download Citation

Abstract

Background

Through data mining the Stanford Microarray Database, the CKS1B transcript was found to be frequently upregulated in hepatocellular carcinomas (HCCs) with low alpha-fetal protein (AFP) expression. Together with SKP2, CKS1B is known to implicate p27^Kip1 protein turnover promoting cell-cycle progression.

Methods

CKS1B, p27^Kip1, and SKP2 were immunostained in 75 HCCs and correlated with clinicopathological features, local recurrence-free survival (LRFS), and overall survival (OS). Silencing of CKS1B and SKP2 with interference short-hairpin RNA (shRNA) was performed in SK-Hep1 and Hep-3B cell lines.

Results

Immunohistochemically, increased CKS1B and SKP2, and attenuated p27^Kip1 were all associated with tumor multiplicity (P < 0.05) and increasing American Joint Committee on Cancer (AJCC) stage (P < 0.05). Overexpression of CKS1B significantly correlated with advanced Okuda stages (P = 0.048) and SKP2 overexpression (P = 0.047). Neither CKS1B nor SKP2 was inversely related to p27^Kip1, which was reinforced by no alteration in p27^Kip1 abundance in HCC-derived cells with CKS1B or SKP2 silencing. Both CKS1B overexpression (P = 0.0011 and P = 0.0017) and p27^Kip1 attenuation (P = 0.0079 and P = 0.0085) were predictive of OS and LRFS, respectively, while SKP2 overexpression was associated with worse OS alone (P = 0.0043). Combined assessment of CKS1B and p27^Kip1 was able to robustly distinguish three prognostically different groups (P < 0.0001). In multivariate comparison, CKS1B overexpression represented the strongest independent adverse prognosticator [OS, P = 0.0235, hazard ratio (HR): 4.193; LRFS, P = 0.0204, HR: 4.262], followed by p27^Kip1 attenuation (OS, P = 0.0320, HR: 2.553; LRFS, P = 0.0262, HR: 2.533).

Conclusions

CKS1B protein overexpression in HCCs is implicated in clinical aggressiveness but not in p27^Kip1 turnover, implying presence of p27^Kip1-independent oncogenic attributes. The combined assessment of CKS1B and p27^Kip1 immunoexpressions effectively risk-stratifies HCCs with different prognoses, which may aid in the management of this deadly malignancy.

Go to Issue Contents