Journal
CANCER RESEARCH
Volume 70, Issue 20, Pages 8233-8246Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-2412
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Funding
- NCI [R01 CA122334, P30 CA016520, T32 CA009140, U54 CA105008]
- NIDDK [P30 DK050306]
- Children's Hospital of Philadelphia
- Cancer Research Institute Immunobiology
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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.
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