| First Author | Blanc V | Year | 2007 |
| Journal | Cancer Res | Volume | 67 |
| Issue | 18 | Pages | 8565-73 |
| PubMed ID | 17875695 | Mgi Jnum | J:124876 |
| Mgi Id | MGI:3722725 | Doi | 10.1158/0008-5472.CAN-07-1593 |
| Citation | Blanc V, et al. (2007) Deletion of the AU-Rich RNA Binding Protein Apobec-1 Reduces Intestinal Tumor Burden in Apcmin Mice. Cancer Res 67(18):8565-73 |
| abstractText | 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 E(2) 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 delta, 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]. |
