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miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis

Oncogene volume 32, pages 341–351 (2013)Cite this article

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Abstract

MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that negatively regulate the expression of their target genes. They are involved in many biological processes, including cell proliferation, apoptosis and differentiation, and are considered as promising new therapeutic targets for cancer. However, the identity of miRNAs involved in apoptosis and their respective targets remain largely unknown. Given the elevated complexity of miRNA regulation of gene expression, we performed a functional screening as an alternative strategy to identify those miRNAs that in lung cancer cells may interfere with the apoptotic process. To this aim, we generated a derivative of the non-small cell lung carcinoma A549 cell line in which caspase-8, a critical upstream initiator of apoptosis, can be activated by administration of the small dimerizer drug AP20187. We found a number of miRNAs that may rescue cell viability from caspase-8 activation. They included miRNAs already described as oncogenic such as miR-17, miR-135 and miR-520, but also some miRNAs such as miR-124-1 and miR-34c for which a tumor-suppressive role has instead been described or expected. Among them, miR-34c-5p markedly increased resistance to paclitaxel-induced apoptosis. We demonstrate that Bmf (Bcl-2-modifying factor) is a target of miR-34c-5p, and that its silencing, together with that of c-myc, a known target of miR-34c-5p, contributes to resistance to apoptosis induced by paclitaxel through p53 downregulation.

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Acknowledgements

This work was supported by funds from CNR, AICR No. 11-0075 (LC), an MIUR grant, MERIT RBNE08YFN3_001 (VdF), AIRC No. 4971 (LC) and No. 10620 (GC), and from the Italian Ministry of Economy and Finance to the CNR for the Project FaReBio di Qualità. We thank ARIAD Pharmaceuticals Inc. for providing the AP20187 dimerizer drug and S Soddu for the pLuc-MDM2 expression vector. We also thank Dr Patrick Martin for help with the development of the inducible death vectors; Dr L Baraldi for technical assistance; CL Esposito, S Camorani, I Iaccarino and P Verde for suggestions and comments; and A Pollice for critically reading the manuscript.

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Authors and Affiliations

  1. Istituto per l’Endocrinologia e l’Oncologia Sperimentale del CNR ‘G Salvatore’, Naples, Italy

    S Catuogno, L Cerchia, G Condorelli & V de Franciscis

  2. Dipartimento di Biologia e Patologia Cellulare e Molecolare, University of Naples ‘Federico II’, Naples, Italy

    S Catuogno & G Condorelli

  3. IRCCS Fondazione SDN, Naples, Italy

    G Romano

  4. CNRS-Université de Nice-Sophia Antipolis, Faculté de Médecine, Nice Cedex 2, France

    P Pognonec

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  1. S Catuogno
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Correspondence to V de Franciscis.

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Catuogno, S., Cerchia, L., Romano, G. et al. miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene 32, 341–351 (2013). https://doi.org/10.1038/onc.2012.51

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