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MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

Oncogene volume 31, pages 4221–4232 (2012)Cite this article

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Abstract

The c-Src kinase regulates cancer cell invasion through inhibitor of DNA binding/differentiation 1 (ID1). Src and ID1 are frequently overexpressed in human lung adenocarcinoma. The current study aimed at identifying microRNAs (miRNAs) involved in the Src-ID1 signaling in lung cancer. Incubation of lung cancer cells with the Src inhibitor saracatinib led to the upregulation of several miRNAs including miR-29b, which was the most highly upregulated miRNA with predicted binding to the ID1 3′-untranslated region (UTR). Luciferase reporter assays confirmed direct binding of miR-29b to the ID1 3′-UTR. Expression of miR-29b suppressed ID1 levels and significantly reduced migration and invasion. Expression of antisense-miR-29b (anti-miR-29b), on the other hand, enhanced ID1 mRNA and protein levels, and significantly increased lung cancer cell migration and invasion, a hallmark of the Src-ID1 pathway. The ectopic expression of ID1 in miR-29b-overexpressing cells was able to rescue the migratory potential of these cells. Both, anti-miR-29b and ID1 overexpression diminished the effects of the Src inhibitors saracatinib and dasatinib on migration and invasion. Saracatinib and dasatinib decreased c-Myc transcriptional repression on miR-29b and led to increased ID1 protein levels, whereas forced expression of c-Myc repressed miR-29b and induced ID1. In agreement, we showed direct recruitment of c-Myc to the miR-29b promoter. miR-29b was significantly downregulated in primary lung adenocarcinoma samples compared with matched alveolar lung tissue, and miR-29b expression was a significant prognostic factor for patient outcome. These results suggest that miR-29b is involved in the Src-ID1 signaling pathway, is dysregulated in lung adenocarcinoma and is a potential predictive marker for Src kinase inhibitors.

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Acknowledgements

Deborah Shan is gratefully acknowledged for excellent technical support. We acknowledge Dr John Minna (UT Southwestern, Medical Center, Dallas, TX, USA) and Dr Yitzhak Zimmer for providing us with cell lines. We thank Wieslawa Blank for support with Western blotting and Dr Daniel Betticher for providing us with primary tumors from the tumor tissue bank. We also thank Dr Jasmin Batliner for support with luciferase assays. We thank AstraZeneca (Manchester, UK) for providing saracatinib. This study was supported by Swiss Cancer League (Grant KLS 02164-02-2008 to OG and MG), the Bernese Cancer League (to MG, OG and MPT), the Werner and Hedy Berger-Janser Foundation of Cancer Research (to MFF and MPT), the Bernese Foundation of Cancer Research, the Marlies-Schwegler Foundation and the Ursula-Hecht-Foundation for Leukemia Research (to MFF).

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Authors and Affiliations

  1. Department of Clinical Research, University of Bern, Bern, Switzerland

    S I Rothschild, M P Tschan, E A Federzoni, R Jaggi & O Gautschi

  2. Department of Medical Oncology, University Hospital Basel, Basel, Switzerland

    S I Rothschild

  3. Department of Medical Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

    M P Tschan & M F Fey

  4. Institute of Pathology, University of Bern, Bern, Switzerland

    M Gugger

  5. Klinik für Onkologie, Luzerner Kantonsspital, Luzern, Switzerland

    O Gautschi

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Correspondence to O Gautschi.

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Rothschild, S., Tschan, M., Federzoni, E. et al. MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma. Oncogene 31, 4221–4232 (2012). https://doi.org/10.1038/onc.2011.578

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