Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice
Jun Zhang, Brigid Stirling, Stephane T. Temmerman, Chi A. Ma, Ivan J. Fuss, Jonathan M.J. Derry, Ashish Jain
Jun Zhang, Brigid Stirling, Stephane T. Temmerman, Chi A. Ma, Ivan J. Fuss, Jonathan M.J. Derry, Ashish Jain
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Research Article Oncology

Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice

Abstract

Cylindromatosis (CYLD) is a deubiquitinating enzyme that is altered in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. However, the regulatory function of CYLD remains unsettled. Here we show that the development of B cells, T cells, and myeloid cells was unaffected in CYLD-deficient mice, but that the activation of these cells with mediators of innate and adaptive immunity resulted in enhanced NF-κB and JNK activity associated with increased TNF receptor–associated factor 2 (TRAF2) and NF-κB essential modulator (NEMO) ubiquitination. CYLD-deficient mice were more susceptible to induced colonic inflammation and showed a dramatic increase in the incidence of tumors compared with controls in a colitis-associated cancer model. These results suggest that CYLD limits inflammation and tumorigenesis by regulating ubiquitination in vivo.

Authors

Jun Zhang, Brigid Stirling, Stephane T. Temmerman, Chi A. Ma, Ivan J. Fuss, Jonathan M.J. Derry, Ashish Jain

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Figure 6

Increased colonic inflammation and tumor development in Cyld–/– mice.

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Increased colonic inflammation and tumor development in Cyld–/– mice. ...
(A) Schematic of the AOM and DSS CAC model. (B) Weight loss during the first cycle of DSS treatment in Cyld–/– and wild-type mice, expressed as percent of the starting weight for each cohort. (C) Histologies of Cyld–/– and wild-type colons, either left untreated or 7 days after the first cycle of DSS treatment. Magnification, ×50. (D) Survival curves of Cyld–/– and wild-type mice (n = 60 per group) injected with AOM followed by DSS. Curves are statistically different (P < 0.001). (E) Incidence and total number of tumors (>0.5 mm) in the colons of Cyld–/– and wild-type mice after administration of AOM followed by DSS. Mice were sacrificed 7 days after the first (left) or the second cycle (right) of DSS treatment. *P < 0.001; Cyld–/– versus wild-type. (F) Typical colon histologies demonstrating broad-based adenocarcinoma in a Cyld–/– section 7 days after the second cycle of DSS treatment. Magnification, ×50.