To define novel pathways that regulate susceptibility to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in non-small cell lung cancer (NSCLC), we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant NSCLC cells, levels of different miRs are increased, and in particular, miR-221 and -222. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. Indeed, transfection with anti-miR-221 and -222 rendered CALU-1-resistant cells sensitive to TRAIL. Conversely, H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3′-UTR of Kit and p27kip1 mRNAs, but interfere with TRAIL signaling mainly through p27kip1. In conclusion, we show that high expression levels of miR-221 and -222 are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets or diagnostic tool for TRAIL resistance in NSCLC. © 2008 Nature Publishing Group All rights reserved.
CITATION STYLE
Garofalo, M., Quintavalle, C., Di Leva, G., Zanca, C., Romano, G., Taccioli, C., … Condorelli, G. (2008). MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene, 27(27), 3845–3855. https://doi.org/10.1038/onc.2008.6
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