Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis encoded by the THBS1 gene, whose promoter is activated by p53. In advanced colorectal cancers (CRC), its expression is sustained or even slightly increased despite frequent loss of p53. Here, we determined that in HCT116 CRC cells, p53 activates the THBS1 primary transcript, but fails to boost THBS1 mRNA or protein levels, implying post-transcriptional regulation by microRNAs. In a global microRNA gain-of-function screen performed in the Dicer-deficient HCT116 variant, several microRNAs negatively regulated THBS1 mRNA and protein levels, one of them being miR-194. Notably, in agreement with published data, p53 upregulated miR-194 expression in THBS1 retrovirus-transduced HCT116 cells, leading to decreased TSP-1 levels. This negative effect was mediated by a single miR-194-complementary site in the THBS1 3'UTR, and its elimination resulted in TSP-1 reactivation, impaired angiogenesis in Matrigel plugs, and reduced growth of HCT116 xenografts. Conversely, transient overexpression of miR-194 in HCT116/THBS1 cells boosted Matrigel angiogenesis, and its stable overexpression in Ras-induced murine colon carcinomas yielded increased microvascular densities and vessel sizes. While the overall contribution of miR-194 to neoplastic growth is context-dependent, p53-induced activation of this GI tract-specific microRNA during ischemia could promote angiogenesis and facilitate tissue repair.
- Received April 1, 2011.
- Revision received September 22, 2011.
- Accepted October 9, 2011.
- Copyright © 2011, American Association for Cancer Research.