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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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 p27Kip1 protein turnover promoting cell-cycle progression.

Methods

CKS1B, p27Kip1, 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 p27Kip1 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 p27Kip1, which was reinforced by no alteration in p27Kip1 abundance in HCC-derived cells with CKS1B or SKP2 silencing. Both CKS1B overexpression (P = 0.0011 and P = 0.0017) and p27Kip1 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 p27Kip1 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 p27Kip1 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 p27Kip1 turnover, implying presence of p27Kip1-independent oncogenic attributes. The combined assessment of CKS1B and p27Kip1 immunoexpressions effectively risk-stratifies HCCs with different prognoses, which may aid in the management of this deadly malignancy.

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Acknowledgment

Special thanks are extended to Dr. WC Hung (Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, Taiwan) for detailed discussion, and for financial support provided by National Science Council (NSC96-2320-B-110-007) to Y.-L. Shiue and partial support from Yuan’s General Hospital (RG06-003) to C.-W. Huang and Chi-Mei Medical Center (CMFHR 9747) to C.-F. Li.

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Authors and Affiliations

  1. Department of Surgery, Yuan’s General Hospital, Kaohsiung, Taiwan

    Ching-Wen Huang, Hong-Yaw Chen & Chung-Chou Juan

  2. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Ching-Wen Huang, Hui-Wen Liu & Yow-Ling Shiue PhD

  3. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan

    Ching-Yih Lin

  4. Department of Pathology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Hsuan-Ying Huang & Yi-Ju Chen

  5. Department of Pathology, Yuan’s General Hospital, Kaohsiung, Taiwan

    Deng-Fuh Shih

  6. Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Chen-Guo Ker

  7. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chen-Guo Ker

  8. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Chi-Ying F. Huang

  9. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

    Chien-Feng Li

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  1. Ching-Wen Huang
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Corresponding author

Correspondence to Yow-Ling Shiue PhD.

Additional information

Ching-Wen Huang, Ching-Yih Lin, Hsuan-Ying Huang contributed equally to this work.

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Huang, CW., Lin, CY., Huang, HY. et al. CKS1B Overexpression Implicates Clinical Aggressiveness of Hepatocellular Carcinomas but Not p27Kip1 Protein Turnover: an Independent Prognosticator with Potential p27Kip1-Independent Oncogenic Attributes?. Ann Surg Oncol 17, 907–922 (2010). https://doi.org/10.1245/s10434-009-0779-8

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  • DOI: https://doi.org/10.1245/s10434-009-0779-8

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