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


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.


SKP2 Rectal cancer Neoadjuvant chemoradiotherapy 



Colorectal cancer




S-phase kinase-associated protein 2



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


Supplementary material

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


  1. 1.
    Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.PubMedCrossRefGoogle Scholar
  2. 2.
    Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24(28):4620–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23.PubMedCrossRefGoogle Scholar
  4. 4.
    National Comprehensive Cancer Network Home Page. Accessed 10 Jan 2011.
  5. 5.
    Hyams DM, Mamounas EP, Petrelli N, Rockette H, Jones J, Wieand HS, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum. Dis Colon Rectum. 1997;40(2):131–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Valentini V, Coco C, Cellini N, Picciocchi A, Genovesi D, Mantini G, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys. 1998;40(5):1067–75.PubMedCrossRefGoogle Scholar
  7. 7.
    Wagman R, Minsky BD, Cohen AM, Guillem JG, Paty PP. Sphincter preservation in rectal cancer with preoperative radiation therapy and coloanal anastomosis: long term follow-up. Int J Radiat Oncol Biol Phys. 1998;42(1):51–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U, et al. P45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999;1(4):207–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Yokoi S, Yasui K, Saito-Ohara F, Koshikawa K, Iizasa T, Fujisawa T, et al. A novel target gene, skp2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002;161(1):207–16.PubMedCrossRefGoogle Scholar
  10. 10.
    Huang HY, Kang HY, Li CF, Eng HL, Chou SC, Lin CN, et al. Skp2 overexpression is highly representative of intrinsic biological aggressiveness and independently associated with poor prognosis in primary localized myxofibrosarcomas. Clin Cancer Res. 2006;12(2):487–98.PubMedCrossRefGoogle Scholar
  11. 11.
    Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY. Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2009;73(1):202–7.PubMedCrossRefGoogle Scholar
  12. 12.
    He QJ, Zeng WF, Sham JST, Xie D, Yang XW, Lin HL, et al. Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients. Cancer Genet Cytogenet. 2003;144(2):112–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY, et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol. 2010;12(5):457–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Li CF, Wang JM, Kang HY, Huang CK, Wang JW, Fang FM, et al. Characterization of gene amplification-driven skp2 overexpression in myxofibrosarcoma: potential implications in tumor progression and therapeutics. Clin Cancer Res. 2012;18(6):1598–610.PubMedCrossRefGoogle Scholar
  15. 15.
    Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell. 2012;149(5):1098–111.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang XC, Tian LL, Tian J, Jiang XY. Overexpression of SKP2 promotes the radiation resistance of esophageal squamous cell carcinoma. Radiat Res. 2011;177(1):52–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  18. 18.
    Uddin S, Ahmed M, Bavi P, El-Sayed R, Al-Sanea N, AbdulJabbar A, et al. Bortezomib (Velcade) induces p27kip1 expression through s-phase kinase protein 2 degradation in colorectal cancer. Cancer Res. 2008;68(9):3379–88.PubMedCrossRefGoogle Scholar
  19. 19.
    Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J, et al. Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001;98(9):5043–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Shapira M, Ben’Izhak O, Linn S, Futerman B, Minkov I, Hershko DD. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005;103(7):1336–46.PubMedCrossRefGoogle Scholar
  21. 21.
    Dworak OKL, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12:19–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin CY, Tian YF, Wu LC, Chen LT, Lin LC, Hsing CH, et al. Rsf-1 expression in rectal cancer: with special emphasis on the independent prognostic value after neoadjuvant chemoradiation. J Clin Pathol. 2012;65(8):687–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002;8(8):2505–11.PubMedGoogle Scholar

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

Personalised recommendations