The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors
2010; American Association for Cancer Research; Volume: 70; Issue: 20 Linguagem: Inglês
10.1158/0008-5472.can-10-2412
ISSN1538-7445
AutoresMichael Dews, Jamie L. Fox, Stacy Hultine, Prema Sundaram, Wenge Wang, Yingqiu Y. Liu, Emma E. Furth, Gregory H. Enders, Wafik S. El‐Deiry, Janell M. Schelter, Michele A. Cleary, Andrei Thomas‐Tikhonenko,
Tópico(s)Cancer, Lipids, and Metabolism
Resumoc-Myc stimulates angiogenesis in tumors through mechanisms that remain incompletely understood. Recent work indicates that c-Myc upregulates the miR-17∼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∼92 promotes angiogenesis and tumor growth. However, clusterin downregulation by miR-17∼92 is indirect. It occurs as a result of reduced transforming growth factor-β (TGFβ) signaling caused by targeting of several regulatory components in this signaling pathway. Specifically, miR-17-5p and miR-20 reduce the expression of the type II TGFβ receptor and miR-18 limits the expression of Smad4. Supporting these results, in human cancer cell lines, levels of the miR-17∼92 primary transcript MIR17HG negatively correlate with those of many TGFβ-induced genes that are not direct targets of miR-17∼92 (e.g., clusterin and angiopoietin-like 4). Furthermore, enforced expression of miR-17∼92 in MIR17HGlow cell lines (e.g., glioblastoma) results in impaired gene activation by TGFβ. Together, our results define a pathway in which c-Myc activation of miR-17∼92 attenuates the TGFβ signaling pathway to shut down clusterin expression, thereby stimulating angiogenesis and tumor cell growth. Cancer Res; 70(20); 8233–46. ©2010 AACR.
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