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Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short report

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Abstract

Purpose

CYLD is a tumor suppressor that has been linked to the development of various human malignancies, including colon cancer. The tumor-suppressing function of CYLD is associated with its deubiquitinating activity, which maps to the carboxyl-terminal region of the protein. In the present study we evaluated the role of intestinal epithelial CYLD in colitis-associated cancer using a conditional mouse CYLD inactivation model.

Methods

In order to evaluate the role of CYLD in intestinal epithelial carcinogenesis, mice (IEC-Cyld Δ9 mice) that carry a mutation that eliminates the deubiquitinating domain of CYLD in intestinal epithelial cells (IEC) were generated by crossing Villin-Cre transgenic mice to previously generated mice carrying a loxP-flanked Cyld exon 9 (Cyld flx9 mice).

Results

We found that IEC-Cyld Δ9 mice did not present spontaneous intestinal abnormalities up to one year of age. However, upon challenge with a combination of genotoxic (AOM) and pro-inflammatory (DSS) agents we found that the number of adenomas in the IEC-Cyld Δ9 mice was dramatically increased compared to the control mice. Inactivation of CYLD in intestinal epithelial cells did not affect the classical nuclear factor-kappaB (NF-κB) and c-Jun kinase (JNK) activation pathways under physiological conditions, suggesting that these pathways do not predispose CYLD-deficient intestinal epithelia to colorectal cancer development before the onset of genotoxic and/or pro-inflammatory stress.

Conclusions

Our findings underscore a critical tumor-suppressing role for functional intestinal epithelial CYLD in colitis-associated carcinogenesis. CYLD expression and its associated pathways in intestinal tumors may be exploited for future prognostic and therapeutic purposes.

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Acknowledgments

This work was supported by intramural funding of the School of Biology of Aristotle University of Thessaloniki and by a scholarship of the Hellenic State Scholarships Foundation (to DNK). The authors gratefully acknowledge the support of the Bodossaki Foundation for the acquisition of laboratory equipment that was used for the imaging and the animal husbandry in the present study.

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Authors and Affiliations

  1. School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece

    Demetrios N. Karatzas, Konstantinos Xanthopoulos, Panorea Kotantaki, Athanasios Pseftogas & George Mosialos

  2. Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece

    Konstantinos Teliousis & Theofilos Poutahidis

  3. Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece

    Eudoxia G. Hatzivassiliou

  4. Biomedical Sciences Research Centre ‘Alexander Fleming’, 16672, Vari, Greece

    Dimitris L Kontoyiannis

Authors
  1. Demetrios N. Karatzas
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  2. Konstantinos Xanthopoulos
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Correspondence to George Mosialos.

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Karatzas, D.N., Xanthopoulos, K., Kotantaki, P. et al. Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short report. Cell Oncol. 39, 287–293 (2016). https://doi.org/10.1007/s13402-016-0279-3

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