Suppression of Latent Transforming Growth Factor (TGF)-β1 Restores Growth Inhibitory TGF-β Signaling through microRNAs

Cancer cells secreting excess latent TGF-beta are often resistant to TGF-beta induced growth inhibition. We observed that RNAi against TGF-beta 1 led to apoptotic death in such cell lines with features that were, paradoxically, reminiscent of TGF-beta signaling activity and that included transiently enhanced SMAD2 and AKT phosphorylation. A comprehensive search in Hela cells for potential microRNA drivers of this mechanism revealed that RNAi against TGF-beta 1 led to induction of pro-apoptotic miR-34a and to a globally decreased oncomir expression. The reduced levels of the oncomirs miR-18a and miR-24 accounted for the observed derepression of two TGF-beta 1 processing factors, thrombospondin-1, and furin, respectively. Our data suggest a novel mechanism in which latent TGF-beta 1, thrombospondin 1, and furin form a microRNA-mediated regulatory feedback loop. For cells with high levels of latent TGF-beta, this provides a potentially widespread mechanism of escape from TGF-beta-mediated growth arrest at the earliest point in the signaling pathway, TGF-beta processing.