The Myc-miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors

c-Myc stimulates angiogenesis in tumors through mechanisms that remain incompletely understood. Recent work indicates that c-Myc upregulates the miR-17 similar to 92 microRNA cluster and downregulates the angiogenesis inhibitor thrombospondin-1, along with other members of the thrombospondin type 1 repeat superfamily. Here, we show that downregulation of the thrombospondin type 1 repeat protein clusterin in cells overexpressing c-Myc and miR-17 similar to 2 promotes angiogenesis and tumor growth. However, clusterin down-regulation by miR-17 similar to 92 is indirect. It occurs as a result of reduced transforming growth factor-beta (TGF beta) signaling caused by targeting of several regulatory components in this signaling pathway. Specifically, miR-17S-5p and miR-20 reduce the expression of the type II TGF beta receptor and miR-18 limits the expression of Smad4. Supporting these results, in human cancer cell lines, levels of the miR-17 similar to 92 primary transcript MIR17HG negatively correlate with those of many TGF beta-induced genes that are not direct targets of miR-17 similar to 92 (e.g., clusterin and angiopoietin-like 4). Furthermore, enforced expression of miR-17 similar to 92 in MIR17H-Glow cell lines (e.g., glioblastoma) results in impaired gene activation by TGF beta. Together, our results define a pathway in which c-Myc activation of miR-17 similar to 92 attenuates the TGF beta signaling pathway to shut down clusterin expression, thereby stimulating angiogenesis and tumor cell growth. Cancer Res; 70(20); 8233-46. (C) 2010 AACR.