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dc.contributor.authorJeon, Y
dc.contributor.authorMiddleton, J
dc.contributor.authorKim, T
dc.contributor.authorLaganà, A
dc.contributor.authorPiovan, C
dc.contributor.authorSecchiero, P
dc.contributor.authorNuovo, G
dc.contributor.authorCui, R
dc.contributor.authorJoshi, P
dc.contributor.authorRomano, G
dc.contributor.authorDi Leva, G
dc.contributor.authorLee, B
dc.contributor.authorSun, H
dc.contributor.authorKim, Y
dc.contributor.authorFadda, P
dc.contributor.authorAlder, H
dc.contributor.authorGarofalo, Michela
dc.contributor.authorCroce, C
dc.date.accessioned2015-07-30T08:57:32Zen
dc.date.available2015-07-30T08:57:32Zen
dc.date.issued2015-06-30en
dc.identifier.citationA set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in Lung cancer. 2015, 112 (26):E3355-64 Proc Natl Acad Scien
dc.identifier.issn1091-6490en
dc.identifier.pmid26080425en
dc.identifier.doi10.1073/pnas.1504630112en
dc.identifier.urihttp://hdl.handle.net/10541/561225en
dc.description.abstractTRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
dc.language.isoenen
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences of the United States of Americaen
dc.titleA set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210en
dc.identifier.journalProceedings of the National Academy of Sciencesen
html.description.abstractTRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.


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