title: Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short report.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Demetrios N
authors.initials: DN
authors.lastname: Karatzas
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Xanthopoulos
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Panorea
authors.initials: P
authors.lastname: Kotantaki
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Pseftogas
authors.affiliation: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Teliousis
authors.affiliation: Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Eudoxia G
authors.initials: EG
authors.lastname: Hatzivassiliou
authors.affiliation: Biomedical Sciences Research Centre 'Alexander Fleming', 16672, Vari, Greece.
authors.forename: Dimitris L
authors.initials: DL
authors.lastname: Kontoyiannis
authors.affiliation: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece. gmosialo@bio.auth.gr.
authors.forename: George
authors.initials: G
authors.lastname: Mosialos
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D003092:Colitis / Q000150:complications* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases
keywords: CYLD; Colon cancer; JNK; NF-κB; Tumor suppressor