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

被引：18

作者：

Huang, Ching-Wen ^{[1
,2
]}

Lin, Ching-Yih ^{[3
]}

Huang, Hsuan-Ying ^{[4
]}

Liu, Hui-Wen ^{[2
]}

Chen, Yi-Ju ^{[4
]}

Shih, Deng-Fuh ^{[5
]}

Chen, Hong-Yaw ^{[1
]}

Juan, Chung-Chou ^{[1
]}

Ker, Chen-Guo ^{[6
,7
]}

Huang, Chi-Ying F. ^{[8
]}

Li, Chien-Feng ^{[9
]}

Shiue, Yow-Ling ^{[2
]}

机构：

[1] Yuans Gen Hosp, Dept Surg, Kaohsiung, Taiwan

[2] Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung 80424, Taiwan

[3] Chi Mei Med Ctr, Dept Internal Med, Div Gastroenterol & Hepatol, Tainan, Taiwan

[4] Chang Gung Univ, Coll Med, Kaohsiung Med Ctr, Chang Gung Mem Hosp,Dept Pathol, Kaohsiung, Taiwan

[5] Yuans Gen Hosp, Dept Pathol, Kaohsiung, Taiwan

[6] Kaohsiung Med Univ Hosp, Dept Surg, Kaohsiung, Taiwan

[7] Kaohsiung Med Univ, Coll Med, Grad Inst Med, Kaohsiung, Taiwan

[8] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan

[9] Chi Mei Med Ctr, Dept Pathol, Tainan, Taiwan

来源：

ANNALS OF SURGICAL ONCOLOGY | 2010年 / 17卷 / 03期

关键词：

UBIQUITIN LIGASE SUBUNIT; GENE-EXPRESSION; CELL-CYCLE; COLORECTAL-CARCINOMA; POOR-PROGNOSIS; BREAST-CANCER; P27; SKP2; PROGRESSION; BINDING;

D O I：

10.1245/s10434-009-0779-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. 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. 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). 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.

引用

页码：907 / 922

页数：16

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