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

  • Research Article
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Tumor Biology

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.

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Abbreviations

CRC:

Colorectal cancer

CRT:

Chemoradiotherapy

SKP2:

S-phase kinase-associated protein 2

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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.

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Author information

Authors and Affiliations

  1. Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan

    Yu-Feng Tian

  2. Department of Health and Nutrition, Chia Nan University of Pharmacy & Science, Tainan, Taiwan

    Yu-Feng Tian

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

    Tzu-Ju Chen & Chien-Feng Li

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

    Ching-Yih Lin & Ming-Jen Sheu

  5. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Ching-Yih Lin

  6. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Li-Tzong Chen, Chien-Feng Li & Shang-Hung Chen

  7. Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan

    Li-Tzong Chen & Shang-Hung Chen

  8. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

    Li-Tzong Chen

  9. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Li-Tzong Chen

  10. Department of Radiation Oncology, Chi-Mei Medical Center, Tainan, Taiwan

    Li-Ching Lin

  11. Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan

    Chung-Hsi Hsing

  12. Department of Radiation Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

    Sung-Wei Lee

  13. Department of Surgery, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

    Hao-Hsien Lee

  14. Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Yow-Ling Shiue

  15. Departments of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Hsuan-Ying Huang

  16. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Chien-Feng Li

  17. Department of Medical Technology, Chung Hwa University of Medical Technology, Tanana, Taiwan

    Chien-Feng Li

  18. Division of Hematology/Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

    Hsin-Yi Pan & Shang-Hung Chen

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  1. Yu-Feng Tian
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  2. Tzu-Ju Chen
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  14. Shang-Hung Chen
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Correspondence to Shang-Hung Chen.

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Tian, YF., Chen, TJ., Lin, CY. et al. SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential. Tumor Biol. 34, 1107–1117 (2013). https://doi.org/10.1007/s13277-013-0652-z

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  • DOI: https://doi.org/10.1007/s13277-013-0652-z

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