Data from Deletion of the AU-Rich RNA Binding Protein Apobec-1 Reduces Intestinal Tumor Burden in <i>Apc<sup>min</sup></i> Mice

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 Apc^min/+ 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 Apc^min/+ apobec-1^−/− mice. Intestinal adenomas from compound Apc^min/+ apobec-1^−/− mice showed a <2-fold increase in Cox-2 mRNA abundance and reduced prostaglandin E₂ content compared with adenomas from the parental Apc^min/+ strain. In addition, there was reduced expression in adenomas from compound Apc^min/+ 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. [Cancer Res 2007;67(18):8565–73]