MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer.
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 p27(kip1) mRNAs, but interfere with TRAIL signaling mainly through p27(kip1). 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.
Garofalo
M
M
Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II, Naples, Italy.
Quintavalle
C
C
Di Leva
G
G
Zanca
C
C
Romano
G
G
Taccioli
C
C
Liu
C G
CG
Croce
C M
CM
Condorelli
G
G
D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000633:toxicity; D015854:Up-Regulation
C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D035683:MicroRNAs; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human