Abstract 3275: miR-194 counterbalances transcriptional activation of the anti-angiogenic factor thrombospondin-1 by p53

作者：Prema Sundaram, Stacy Hultine, Lauren M. Smith, Dauren Biyashev, Janell M. Schelter, Michele A. Cleary, Olga V. Volpert, Andrei Thomas‐Tikhonenko, Andrei Thomas‐Tikhonenko · 发表于：Cancer Research · 年份：2011 · DOI：10.1158/1538-7445.am2011-3275 · 被引用次数：1 · 研究领域：Angiogenesis and VEGF in Cancer

Abstract Thrombospondin-1 (TSP-1) is a key endogenous inhibitor of angiogenesis, negatively regulated by oncogenes (e.g., c-Myc) and transcriptionally activated by the key tumor suppressor p53 (1). Yet in some cancers, such as colon adenocarcinomas, tumor progression accompanied by the loss of p53 does not result in TSP-1 down-regulation (2, 3). This paradox could involve promoter-independent mechanisms, for example microRNA-mediated regulation. In order to test this hypothesis, we conducted a global screen for microRNAs that regulate TSP-1 levels. Gain-of-function experiments and microarray data showed that in addition to the previously identified mir-17-92 cluster members (4, 5), several other miRs, including let-7, mir-199a-3p, mir-218 and miR-194, downregulate TSP-1. mir-194 was of particular interest, since its expression is known to be largely colon-specific (6), maintained by p53 and thus frequently reduced in advanced cancers (7). This reduced miR-194 expression could account for unexpectedly high TSP-1 levels in p53-null tumors. Indeed, mir-194 inhibition with antisense 2’-O-methyl ribonucleotides in p53-sufficient colon cancer cell lines strongly restored TSP-1 levels. Conversely, miR-194 mimics reduced TSP-1 expression at both RNA and protein levels. Furthermore, dual luciferase sensor assay demonstrated that this regulation was mediated by the single mir-194 site in the 3’UTR of the thbs1 gene. We then set up a retroviral transduction-based system to test the invo...