32 Scopus citations

Abstract

The RNA-specific cytidine deaminase apobec-1 is an AU-rich RNA binding protein that binds the 3′ untranslated region (UTR) of cyclooxygenase-2 (Cox-2) mRNA and stabilizes its turnover in vitro. Cox-2 overexpression accompanies intestinal adenoma formation in both humans and mice. Evidence from both genetic deletion studies as well as from pharmacologic inhibition has implicated Cox-2 in the development of intestinal adenomas in experimental animals and in adenomas and colorectal cancer in humans. Here, we show that small intestinal adenoma formation is dramatically reduced in compound Apc min/+ apobec-1-/- mice when compared with the parental Apcmin/+ strain. This reduced tumor burden was found in association with increased small intestinal apoptosis and reduced proliferation in small intestinal crypt-villus units from compound Apcmin/+ apobec-1 -/- mice. Intestinal adenomas from compound Apcmin/+ apobec-1-/- mice showed a <2-fold increase in Cox-2 mRNA abundance and reduced prostaglandin E2 content compared with adenomas from the parental Apcmin/+ strain. In addition, there was reduced expression in adenomas from compound Apcmin/+ apobec-1-/- mice of other mRNAs (including epidermal growth factor receptor, peroxisome proliferator-activated receptor δ, prostaglandin receptor EP4, and c-myc), each containing the apobec-1 consensus binding site within their 3′-UTR. Adenovirus-mediated apobec-1 introduction into HCA-7 (colorectal cancer) cells showed a dose-dependent increase in Cox-2 protein and stabilization of endogenous Cox-2 mRNA. These findings suggest that deletion of apobec-1, by modulating expression of AU-rich RNA targets, provides an important mechanism for attenuating a dominant genetic restriction point in intestinal adenoma formation.

Original languageEnglish
Pages (from-to)8565-8573
Number of pages9
JournalCancer research
Volume67
Issue number18
DOIs
StatePublished - Sep 15 2007

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