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RETRACTED ARTICLE: EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers

Nature Medicine volume 18, pages 74–82 (2012)Cite this article

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This article was retracted on 04 October 2022

A Corrigendum to this article was published on 07 January 2014

This article has been updated

Abstract

The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.

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Figure 1: TKI-regulated miRNA targets.
Figure 2: MET-miRNA coexpression analysis.
Figure 3: Gefitinib downregulates miR-221, miR-222, miR-30b and miR-30c.
Figure 4: MiR-30b, miR-30c, miR-221, miR-222, miR-103 and miR-203 regulate gefitinib sensitivity.
Figure 5: MiR-103 and miR-203 inhibit the migration and proliferation of NSCLCs.
Figure 6: MET induces epithelial-mesenchymal transition.

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Change history

  • 30 March 2022

    Editor’s Note: we are alerting readers that concerns have been raised about the integrity of images in this paper. These issues are currently being reviewed by the editors. A further editorial response will follow upon conclusion of the review.

  • 19 November 2013

     In the version of this article initially published, the actin loading control of the western blot in Figure 1a was a rotated duplicate of the actin control in Figure 1h. The authors have not been able to provide the original control data, but they have repeated the experiment and have provided new blots (Fig. 1) that are now published as part of the correction notices linked to the HTML version and attached to the PDF version of the article. The original blots remain in both online versions of the article. In addition, Figure 6g contained a spliced gel that has now been corrected in the HTML and PDF versions of the article.

  • 07 January 2014

    A Correction to this paper has been published: https://doi.org/10.1038/nm0114-103

  • 04 October 2022

    This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41591-022-02044-2

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Acknowledgements

We thank K. Huebner and S. Lutz for revisions to the paper and P. Fadda and S. Miller for qRT-PCR assistance. We also thank K. Sergott and Ventana Medical Systems for supplying the immunohistochemistry reagents used in this study. M. Nuovo (The Ohio State University Medical Center) kindly provided the photomicroscopy work. We are grateful for research support from The Ohio State University Targeted Investment in Excellence Award, the US National Institutes of Health grant CA113001 and the Kimmel Scholar Award (M.G.).

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Author notes

  1. Michela Garofalo, Giulia Romano and Gianpiero Di Leva: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA

    Michela Garofalo, Gianpiero Di Leva, Gerard Nuovo, Young-Jun Jeon, Apollinaire Ngankeu, Jin Sun, Francesca Lovat, Hansjuerg Alder, Luciano Cascione, Stefano Volinia & Carlo M Croce

  2. Istituto Di Ricovero e Cura a Carattere Scientifico Studio Diagnostica Nucleare (SDN), Naples, Italy

    Giulia Romano

  3. Department of Cellular and Molecular Biology and Pathology, Institute of Experimental Endocrinology and Oncology, Consiglio Nazionale delle Ricerche (IEOS-CNR), Faculty of Biotechnological Science, 'Federico II' University of Naples, Napoli, Italy

    Gerolama Condorelli

  4. Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Jeffrey A Engelman

  5. Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Mayumi Ono

  6. Department of Pulmonary and Critical Care Medicine, University of Ulsan, Seoul, Korea

    Jin Kyung Rho

  7. Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy

    Luciano Cascione

  8. Department of Cellular and Integrated Physiology, Medical Sciences Program, Indiana University School of Medicine and the Indiana University Simon Cancer Center, Bloomington, Indiana, USA

    Kenneth P Nephew

Authors
  1. Michela Garofalo
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Contributions

M.G. designed the research. M.G., G.R., G.D.L., Y.-J.J., A.N. and F.L. performed the research. G.D.L. and J.S. conducted the mouse experiments. G.N. performed the IHC and ISH experiments. H.A. performed the microarray experiments and analyses. K.P.N. and G.C. provided discussions and advice. J.A.E., M.O. and J.K.R. provided cells with acquired gefitinib resistance. S.V. and L.C. performed bioinformatics analyses. M.G. and C.M.C. wrote the paper.

Corresponding author

Correspondence to Carlo M Croce.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary Results, Supplementary Methods, Supplementary Figures 1–16 and Supplementary Tables 1 and 2 (PDF 3184 kb)

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Garofalo, M., Romano, G., Di Leva, G. et al. RETRACTED ARTICLE: EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 18, 74–82 (2012). https://doi.org/10.1038/nm.2577

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  • DOI: https://doi.org/10.1038/nm.2577

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