MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

To de. ne 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 pro. ling 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 p27(kip1) mRNAs, but interfere with TRAIL signaling mainly through p27kip1. In conclusion, we showthat 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.