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Tumor Biology

, Volume 34, Issue 2, pp 1107–1117 | Cite as

SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential

  • Yu-Feng Tian
  • Tzu-Ju Chen
  • Ching-Yih Lin
  • Li-Tzong Chen
  • Li-Ching Lin
  • Chung-Hsi Hsing
  • Sung-Wei Lee
  • Ming-Jen Sheu
  • Hao-Hsien Lee
  • Yow-Ling Shiue
  • Hsuan-Ying Huang
  • Hsin-Yi Pan
  • Chien-Feng Li
  • Shang-Hung Chen
Research Article

Abstract

The S-phase kinase-associated protein 2 (SKP2) oncoprotein is an E3 ubiquitin ligase. Overexpression of SKP2 was found in various human cancers, including colorectal cancers, but its potential role as a prognostic marker after neoadjuvant chemoradiotherapy (CRT) and for therapeutic intervention in rectal cancers is unknown. This study examined the correlation of SKP2 expression in the prognosis of rectal cancer patients and the viability of colorectal cancer cells treated with CRT. SKP2 immunoexpression was retrospectively assessed in pretreatment biopsies of 172 rectal cancer patients treated with neoadjuvant CRT followed by surgery. Results were correlated with clinicopathological features, therapeutic responses, and patient survival. Pharmacologic assays were used to evaluate the therapeutic relevance of Bortezomib in two colorectal cancer cell lines (HT-29 and SW480). High expression of SKP2 was correlated with the advanced Post-Tx nodal status (p = 0.002), Post-Tx International Union for Cancer Control stage (p = 0.002), and a lower-degree tumor regression grade (p < 0.001). Moreover, high expression of SKP2 (p = 0.027, hazard ratio 3.21) was an independent prognostic factor for local recurrence-free survival. In vitro, Bortezomib downregulated SKP2 expression, induced caspase activation, and decreased the viability of colorectal cancer cells with or without a combination with fluorouracil. Bortezomib also promoted caspase activation and gamma-H2AX formation in colorectal cancer cells concurrently treated with CRT. High expression of SKP2 was associated with a poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CRT. In the presence of chemotherapy with or without radiotherapy, the promoted sensitivity of colorectal cancer cells to Bortezomib with an SKP2-repressing effect indicated that it is a potential therapeutic target.

Keywords

SKP2 Rectal cancer Neoadjuvant chemoradiotherapy 

Abbreviations

CRC

Colorectal cancer

CRT

Chemoradiotherapy

SKP2

S-phase kinase-associated protein 2

Notes

Acknowledgments

This work was supported in part by grants from the National Science Council, Taiwan (NSC99-2320-B-384-001-MY2 to CF Li) and Department of Health, Taiwan (DOH99-TD-C-111-004). The authors are grateful to the Translational Research Laboratory of Human Cancers of Chi-Mei Medical Center for providing critical technical assistance.

Conflicts of interest

None

Supplementary material

13277_2013_652_MOESM1_ESM.doc (32 kb)
ESM 1 (DOC 31 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Yu-Feng Tian
    • 1
    • 2
  • Tzu-Ju Chen
    • 3
  • Ching-Yih Lin
    • 4
    • 5
  • Li-Tzong Chen
    • 6
    • 7
    • 8
    • 9
  • Li-Ching Lin
    • 10
  • Chung-Hsi Hsing
    • 11
  • Sung-Wei Lee
    • 12
  • Ming-Jen Sheu
    • 4
  • Hao-Hsien Lee
    • 13
  • Yow-Ling Shiue
    • 14
  • Hsuan-Ying Huang
    • 15
  • Hsin-Yi Pan
    • 18
  • Chien-Feng Li
    • 3
    • 6
    • 16
    • 17
  • Shang-Hung Chen
    • 6
    • 7
    • 18
  1. 1.Division of General Surgery, Department of SurgeryChi-Mei Medical CenterTainanTaiwan
  2. 2.Department of Health and NutritionChia Nan University of Pharmacy & ScienceTainanTaiwan
  3. 3.Department of PathologyChi-Mei Medical CenterTainanTaiwan
  4. 4.Division of Gastroenterology and Hepatology, Department of Internal MedicineChi-Mei Medical CenterTainanTaiwan
  5. 5.Department of Leisure, Recreation, and Tourism ManagementSouthern Taiwan University of Science and TechnologyTainanTaiwan
  6. 6.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  7. 7.Institute of Clinical Pharmacy and Pharmaceutical SciencesNational Cheng Kung UniversityTainanTaiwan
  8. 8.Department of Internal MedicineNational Cheng Kung University HospitalTainanTaiwan
  9. 9.Department of Internal MedicineKaohsiung Medical University HospitalKaohsiungTaiwan
  10. 10.Department of Radiation OncologyChi-Mei Medical CenterTainanTaiwan
  11. 11.Department of AnesthesiologyChi-Mei Medical CenterTainanTaiwan
  12. 12.Department of Radiation Oncology, Department of Internal MedicineChi-Mei Medical Center, LiouyingTainanTaiwan
  13. 13.Department of SurgeryChi-Mei Medical Center, LiouyingTainanTaiwan
  14. 14.Institute of Biomedical ScienceNational Sun Yat-Sen UniversityKaohsiungTaiwan
  15. 15.Departments of PathologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  16. 16.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  17. 17.Department of Medical TechnologyChung Hwa University of Medical TechnologyTananaTaiwan
  18. 18.Division of Hematology/Oncology, Department of Internal MedicineChi-Mei Medical Center, LiouyingTainanTaiwan

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