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Tumor Biology

, Volume 37, Issue 7, pp 8731–8739 | Cite as

Decreased CK1δ expression predicts prolonged survival in colorectal cancer patients

  • Julia Richter
  • Steven Rudeck
  • Anna-Laura Kretz
  • Klaus Kramer
  • Steffen Just
  • Doris Henne-Bruns
  • Andreas Hillenbrand
  • Frank Leithäuser
  • Johannes Lemke
  • Uwe Knippschild
Original Article

Abstract

Cancers arising from the large intestine or rectum are called colorectal cancer (CRC) and represent the fourth leading cause of cancer-related death worldwide. Since casein kinase 1 (CK1) isoforms are involved in many cellular processes and have been reported to be deregulated in various tumor entities, CK1 has become an interesting drug target. In this study, we examined the potential of CK1δ expression levels in tumor tissue of CRC patients as a prognostic biomarker. We show by quantitative RNA expression analyses that decreased CK1δ expression levels in tumor tissue predict prolonged survival rates. Random sampling of CK1δ stained tumor tissue indicates that CK1δ gene expression corresponds with CK1δ protein expression. Especially in low grade (grade 1, grade 2) and in UICC II/III classified tumors decreased CK1δ RNA levels correlate with significantly improved survival rates when the tumor was located in the right colon. We furthermore found gender-specific differences within these subgroups, revealing most significant increase in overall survival rates in male patients with tumors in right colon expressing low levels of CK1δ RNA. Results become even clearer, when only male patients over 50 years were considered. Together, these findings support the assumption that CK1δ might be a prognostic biomarker for CRC thereby providing an interesting drug target for the development of new therapy concepts.

Keywords

CK1δ Colorectal cancer Prognosis Outcome Survival Prognostic marker 

Notes

Acknowledgments

The authors would like to thank Dr. Pengfei Xu, Annette Blatz, and Vanessa Alscher for their excellent technical assistance.

Work in the lab of Uwe Knippschild is funded by the Deutsche Forschungsgemeinschaft (DFG) (KN356/6-1).

Compliance with ethical standards

The study was performed with the permission of the independent local ethics committee of the University of Ulm (approval 268/2008).

Conflicts of interest

None

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

13277_2015_4745_MOESM1_ESM.pdf (692 kb)
ESM 1 (PDF 691 kb)

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41.CrossRefPubMedGoogle Scholar
  3. 3.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Scartozzi M, Pierantoni C, Berardi R, Antognoli S, Bearzi I, Cascinu S. Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer. Anal Quant Cytol Histol. 2006;28(2):61–8.PubMedGoogle Scholar
  5. 5.
    Ellis LM, Takahashi Y, Liu W, Shaheen RM. Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist. 2000;5 Suppl 1:11–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Knippschild U, Krueger M, Richter J, Xu P, García-Reyes B, Peifer C et al. The CK1 family: contribution to cellular stress response and its role in carcinogenesis. Front Oncol. 2014;4(96). doi: 10.3389/fonc.2014.00096.
  7. 7.
    Schittek B, Sinnberg T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. Mol Cancer. 2014;13:231.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Umar S, Wang Y, Morris AP, Sellin JH. Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia. Am J Physiol Gastrointest Liver Physiol. 2007;292(2):G599–607.CrossRefPubMedGoogle Scholar
  9. 9.
    Tsai IC, Woolf M, Neklason DW, Branford WW, Yost HJ, Burt RW, et al. Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism. Int J Cancer. 2007;120(5):1005–12.CrossRefPubMedGoogle Scholar
  10. 10.
    Richter J, Ullah K, Xu P, Alscher V, Blatz A, Peifer C, et al. Effects of altered expression and activity levels of CK1delta and varepsilon on tumor growth and survival of colorectal cancer patients. Int J Cancer. 2015;136(12):2799–810.CrossRefPubMedGoogle Scholar
  11. 11.
    Burzio V, Antonelli M, Allende CC, Allende JE. Biochemical and cellular characteristics of the four splice variants of protein kinase CK1alpha from zebrafish (Danio rerio). J Cell Biochem. 2002;86(4):805–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Fu Z, Chakraborti T, Morse S, Bennett GS, Shaw G. Four casein kinase I isoforms are differentially partitioned between nucleus and cytoplasm. Exp Cell Res. 2001;269(2):275–86.CrossRefPubMedGoogle Scholar
  13. 13.
    Green CL, Bennett GS. Identification of four alternatively spliced isoforms of chicken casein kinase I alpha that are all expressed in diverse cell types. Gene. 1998;216(1):189–95.CrossRefPubMedGoogle Scholar
  14. 14.
    Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 2005;17(6):675–89.CrossRefPubMedGoogle Scholar
  15. 15.
    Sobin LH, Gospodarowicz MK, Wittekind C. In: Sobin LH, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 7th ed. New York: Wiley-Liss Inc; 2009. p. 100–5.Google Scholar
  16. 16.
    Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumors of the digestive system. World Health Organization Classification of Tumours. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2010.Google Scholar
  17. 17.
    de Kok JB, Roelofs RW, Giesendorf BA, Pennings JL, Waas ET, Feuth T, et al. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab Invest. 2005;85(1):154–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Brockschmidt C, Hirner H, Huber N, Eismann T, Hillenbrand A, Giamas G, et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut. 2008;57(6):799–806.CrossRefPubMedGoogle Scholar
  19. 19.
    Stoter M, Bamberger AM, Aslan B, Kurth M, Speidel D, Loning T, et al. Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. Oncogene. 2005;24(54):7964–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Cheong JK, Virshup DM. Casein kinase 1: complexity in the family. Int J Biochem Cell Biol. 2011;43(4):465–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Maritzen T, Lohler J, Deppert W, Knippschild U. Casein kinase I delta (CKIdelta) is involved in lymphocyte physiology. Eur J Cell Biol. 2003;82(7):369–78.CrossRefPubMedGoogle Scholar
  22. 22.
    Cheong JK, Nguyen TH, Wang H, Tan P, Voorhoeve PM, Lee SH, et al. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1delta/varepsilon and Wnt/beta-catenin independent inhibition of mitotic spindle formation. Oncogene. 2011;30(22):2558–69.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Richter J, Bischof J, Zaja M, Kohlhof H, Othersen O, Vitt D, et al. Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1delta and epsilon with nanomolar inhibitory activity on cancer cell proliferation. J Med Chem. 2014;57(19):7933–46.CrossRefPubMedGoogle Scholar
  24. 24.
    Cooper GS, Yuan Z, Landefeld CS, Johanson JF, Rimm AA. A national population-based study of incidence of colorectal cancer and age. Implications for screening in older Americans. Cancer. 1995;75(3):775–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Okamoto M, Shiratori Y, Yamaji Y, Kato J, Ikenoue T, Togo G, et al. Relationship between age and site of colorectal cancer based on colonoscopy findings. Gastrointest Endosc. 2002;55(4):548–51.CrossRefPubMedGoogle Scholar
  26. 26.
    Slattery ML, Friedman GD, Potter JD, Edwards S, Caan BJ, Samowitz W. A description of age, sex, and site distributions of colon carcinoma in three geographic areas. Cancer. 1996;78(8):1666–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol. 2008;15(9):2388–94.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    McCashland TM, Brand R, Lyden E, de Garmo P. Gender differences in colorectal polyps and tumors. Am J Gastroenterol. 2001;96(3):882–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88.CrossRefPubMedGoogle Scholar
  30. 30.
    Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, et al. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev. 2003;12(8):755–62.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Julia Richter
    • 1
  • Steven Rudeck
    • 2
  • Anna-Laura Kretz
    • 1
  • Klaus Kramer
    • 1
  • Steffen Just
    • 2
  • Doris Henne-Bruns
    • 1
  • Andreas Hillenbrand
    • 1
  • Frank Leithäuser
    • 3
  • Johannes Lemke
    • 1
  • Uwe Knippschild
    • 1
  1. 1.Department of General and Visceral Surgery, Surgery CentreUlm University HospitalUlmGermany
  2. 2.Department of Internal Medicine IIUlm University HospitalUlmGermany
  3. 3.Department of PathologyUlm University HospitalUlmGermany

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