Carcinogenesis Advance Access originally published online on January 9, 2006
Carcinogenesis 2006 27(5):956-961; doi:10.1093/carcin/bgi335
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Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-
B activation and oxidative stress
1 Division of Gastroenterology and Liver Research Center and 2 Department of Pathology, Brown Medical School and Rhode Island Hospital, Providence, RI 02903, USA and 3 First Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
* To whom correspondence should be addressed at: Liver Research Center, 55 Claverick Street, Room 413, Providence, RI 02903, USA. Tel: +1 401 444 2536; Fax: +1 401 444 2939; Email: gbaffy{at}brown.edu
Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-
B), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2–/– mice develop more aberrant crypt foci and colon tumors than Ucp2+/+ littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8–12). This effect is primarily seen in the proximal colon of Ucp2–/– mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-B activation (increased levels of phosphorylated IB and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2'-deoxy-uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.
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