A set of NF-?B-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Jeon, Young-Jun; Middleton, Justin; Kim, Taewan; Laganà, Alessandro; Piovan, Claudia; Secchiero, Paola; Nuovo, Gerard J.; Cui, Ri; Joshi, Pooja; Romano, Giulia; Di Leva, Gianpiero; Lee, Bum-Kyu; Sun, Hui-Lung; Kim, Yonghwan; Fadda, Paolo; Alder, Hansjuerg; Garofalo, Michela; Croce, Carlo M.

doi:10.1073/pnas.1504630112

A set of NF-?B-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Jeon, Young-Jun; Middleton, Justin; Kim, Taewan; Laganà, Alessandro; Piovan, Claudia; Secchiero, Paola; Nuovo, Gerard J.; Cui, Ri; Joshi, Pooja; Romano, Giulia; Di Leva, Gianpiero; Lee, Bum-Kyu; Sun, Hui-Lung; Kim, Yonghwan; Fadda, Paolo; Alder, Hansjuerg; Garofalo, Michela; Croce, Carlo M.

Authors

Young-Jun Jeon

Justin Middleton

Taewan Kim

Alessandro Laganà

Claudia Piovan

Paola Secchiero

Gerard J. Nuovo

Ri Cui

Pooja Joshi

Giulia Romano

Gianpiero Di Leva g.dileva@keele.ac.uk

Bum-Kyu Lee

Hui-Lung Sun

Yonghwan Kim

Paolo Fadda

Hansjuerg Alder

Michela Garofalo

Carlo M. Croce

Abstract

TRAIL (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-?B, 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-?B, 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-?B inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.

Journal Article Type	Article
Acceptance Date	Jun 15, 2015
Publication Date	Jun 30, 2015
Journal	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Print ISSN	0027-8424
Publisher	National Academy of Sciences
Peer Reviewed	Peer Reviewed
Volume	112
Issue	26
Pages	E3355 - E3364
DOI	https://doi.org/10.1073/pnas.1504630112
Keywords	microRNAs; acquired TRAIL-resistance; lung cancer
Publisher URL	https://www.pnas.org/content/112/26/E3355/tab-article-info