Abstract 4349: Regulation of proliferation and platelet-derived growth factor expression in desmoid tumors by microRNA-29

Abstract

Abstract Desmoid tumors (DT), also called aggressive fibromatosis, are a rare, locally invasive soft tissue tumors. While DTs harbor mutations that activate β-catenin, a major effector molecule of canonical Wnt signaling, they also display elevated levels of both Platelet-Derived Growth Factor Receptor Beta (PDGFRβ) and its PDGF-B ligand. We hypothesize that active PDGFRβ signaling maintains DT progression. We studied the effect of PDGFRβ inhibition on DT growth. Primary cultures of DTs treated with the PDGFRβ inhibitor Sunitinib show a decrease in proliferation rate as measured by bromodeoxyuridine (BrdU) incorporation assay. In vivo, Sunitinib treatment of Apc1638N/+ mice, a mouse model of DT, also decreased the number and size of tumors. To investigate the relationship of β-catenin activation and PDGFRβ activation, we treated human skin fibroblasts with Wnt3a to activate canonical Wnt signaling, and utilized transgenic murine skin fibroblasts harboring an activated form of β-catenin. In both systems, PDGF-B ligand expression increased both at the mRNA and protein level. However, this increase was not observed immediately, suggesting an indirect mode of regulation. The PDGF-B gene contains a conserved microRNA-29 (miR29) binding site in its 3′ untranslated region. In silico miRacts analysis of five independent DT microarray studies predicted miR29 family deregulation. As such, we studied whether miR29 deregulation in DT leads to PDGF-B overexpression and tumor proliferation. By performing quantitative PCR on human DT samples, we observed that the levels of mature forms of all miR29 family members (MIR29A, B, and C) are significantly down-regulated. Overexpressing miR29 in DT cells decreases PDGF-B ligand levels as well as BrdU incorporation rate. Finally, β-catenin-induced modulation of the PDGF-B ligand is abrogated upon inhibiting miR29. Taken together, these data suggest that PDGFRβ signaling is a potentially important pathway in DT progression. PDGFRβ may be linked to β-catenin by the novel discovery of microRNA-29 down-regulation in DT tumors. This work will offer new perspectives on the molecular biology underlying DT development and help identify novel targets for therapy. Citation Format: Mushriq Al-Jazrawe, Raymond Poon, Jessica Liu, Benjamin Alman. Regulation of proliferation and platelet-derived growth factor expression in desmoid tumors by microRNA-29. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4349. doi:10.1158/1538-7445.AM2014-4349