World Journal of Surgery

, Volume 42, Issue 11, pp 3771–3778 | Cite as

Analysis of Potential Alterations Affecting SETBP1 as a Novel Contributing Mechanism to Inhibit PP2A in Colorectal Cancer Patients

  • Blanca Torrejón
  • Ion CristóbalEmail author
  • Cristina Caramés
  • Iván Prieto-Potín
  • Cristina Chamizo
  • Andrea Santos
  • Marta Sanz-Alvarez
  • Roberto Serna-Blasco
  • Melania Luque
  • Juan Madoz-Gúrpide
  • Federico Rojo
  • Jesús García-FoncillasEmail author
Original Scientific Report



The functional loss of the tumor suppressor protein phosphatase 2A (PP2A) occurs in a wide variety of human cancers including colorectal cancer (CRC), and SET overexpression has been reported as a key contributing mechanism to inhibit PP2A. Although SET binding protein 1 (SETBP1) overexpression and gain of function mutations have been described in several hematological malignancies as common events that increase the expression levels of the PP2A inhibitor SET, thereby leading to PP2A inactivation, the potential existence of SETBP1 alterations in CRC still remains unexplored.


We studied the expression profile of SETBP1 by Western blot in a set of CRC cell lines and patient samples. Moreover, we performed co-immunoprecipitation assays to analyze the formation of the previously reported SETBP1–SET–PP2A inhibitory complex. Furthermore, we evaluated the mutational status of SETBP1 by pyrosequencing assays in a cohort of 55 CRC patients with metastatic disease after the immunohistochemical characterization of SET and p-PP2A expression in this cohort.


We found high SETBP1 expression in several CRC lines but only in two of the patients analyzed. In addition, we demonstrated the formation of the SETBP1–SET–PP2A heterotrimeric complex in CRC cells. However, we failed to detect SETBP1 mutations in any of the CRC patient samples included in the study.


Our results suggest that SETBP1 expression is mainly similar o lower in colorectal cancer tissue compared to normal colonic mucosa. However, its overexpression is a low prevalent alteration which could contribute to inhibit PP2A in CRC through the formation of a SETBP1–SET–PP2A complex in some CRC patients. Moreover, SETBP1 mutations are, if exist, rare events in CRC patients.



This work was supported by PI15/00934 and PI16/01468 grants from “Instituto de Salud Carlos III FEDER”, Spain. B.T. is supported by “Fundación Conchita Rábago de Jiménez Díaz”.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

268_2018_4684_MOESM1_ESM.ppt (240 kb)
Supplementary material 1 (PPT 240 kb)
268_2018_4684_MOESM2_ESM.ppt (265 kb)
Supplementary material 2 (PPT 265 kb)


  1. 1.
    Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502CrossRefGoogle Scholar
  2. 2.
    Linnekamp JF, Wang X, Medema JP et al (2015) Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes. Cancer Res 75:245–249CrossRefGoogle Scholar
  3. 3.
    Cristóbal I, Blanco FJ, García-Orti L et al (2010) SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood 115:615–625CrossRefGoogle Scholar
  4. 4.
    Ruvolo PP (2016) The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance. BBA Clin 6:87–99CrossRefGoogle Scholar
  5. 5.
    Rincón R, Cristóbal I, Zazo S et al (2015) PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. Oncotarget 6:4299–4314CrossRefGoogle Scholar
  6. 6.
    Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353:417–439CrossRefGoogle Scholar
  7. 7.
    Zolnierowicz S (2000) Type 2A protein phosphatase, the complex regulator of numerous signalling pathways. Biochem Pharmacol 60:1225–1235CrossRefGoogle Scholar
  8. 8.
    Xie F, Bao X, Yu J et al (2015) Disruption and inactivation of the PP2A complex promotes the proliferation and angiogenesis of hemangioma endothelial cells through activating AKT and ERK. Oncotarget 6:25660–25676PubMedPubMedCentralGoogle Scholar
  9. 9.
    Grech G, Baldacchino S, Saliba C et al (2016) Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutics options. Tumour Biol 37:11691–11700CrossRefGoogle Scholar
  10. 10.
    Seo SB, McNamara P, Heo S et al (2001) Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the SET oncoprotein. Cell 104:119–130CrossRefGoogle Scholar
  11. 11.
    ten Klooster JP, Iv Leeuwen, Scheres N et al (2009) Rac-1 induced cell migration requires membrane recruitment of the nuclear oncogene SET. EMBO J 26:336–345CrossRefGoogle Scholar
  12. 12.
    Eichhorn PJ, Creyghton MP, Bernards R (2009) Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795:1–15PubMedGoogle Scholar
  13. 13.
    Piazza R, Valletta S, Winkelmann N et al (2013) Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 45:18–24CrossRefGoogle Scholar
  14. 14.
    Makishima H, Yoshida K, Nguyen N et al (2013) Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 45:942–946CrossRefGoogle Scholar
  15. 15.
    Patnaik MM, Itzykson R, Lasho TL et al (2014) ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28:2206–2212CrossRefGoogle Scholar
  16. 16.
    Kanagal-Shamanna R, Luthra R, Yin CC et al (2016) Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS. Oncotarget 7:14251–14258CrossRefGoogle Scholar
  17. 17.
    Bresolin S, De Filippi P, Vendemini F et al (2016) Mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia: a report from the Italian AIEOP study group. Oncotarget 7:28914–28919CrossRefGoogle Scholar
  18. 18.
    Cristóbal I, Manso R, Rincón R et al (2014) PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol Cancer Ther 13:938–947CrossRefGoogle Scholar
  19. 19.
    Cristóbal I, Rincón R, Manso R et al (2015) Deregulation of the PP2A inhibitor SET shows promising therapeutic implications and determines poor clinical outcome in patients with metastatic colorectal cancer. Clin Cancer Res 21:347–356CrossRefGoogle Scholar
  20. 20.
    Cristóbal I, Caramés C, Rincón R et al (2016) Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer. Oncotarget 8:40169–40180PubMedCentralGoogle Scholar
  21. 21.
    Nacional Center for Biotechnology Information. Accessed 17 Nov 2016
  22. 22.
    Cristóbal I, Manso R, Rincón R et al (2014) Phosphorylated protein phosphatase 2A determines poor outcome in patients with metastatic colorectal cancer. Br J Cancer 111:756–762CrossRefGoogle Scholar
  23. 23.
    Tang Z, Li C, Kang B et al (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2018

Authors and Affiliations

  • Blanca Torrejón
    • 1
  • Ion Cristóbal
    • 1
    Email author
  • Cristina Caramés
    • 1
  • Iván Prieto-Potín
    • 2
  • Cristina Chamizo
    • 1
  • Andrea Santos
    • 1
  • Marta Sanz-Alvarez
    • 2
  • Roberto Serna-Blasco
    • 1
  • Melania Luque
    • 2
  • Juan Madoz-Gúrpide
    • 2
  • Federico Rojo
    • 2
  • Jesús García-Foncillas
    • 1
    Email author
  1. 1.Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez DiazAutonomous University of Madrid, University Hospital “Fundación Jiménez Diaz”MadridSpain
  2. 2.Pathology DepartmentAutonomous University of Madrid, University Hospital “Fundación Jiménez Diaz”MadridSpain

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