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MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression

Oncogene volume 32, pages 2984–2991 (2013)Cite this article

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Abstract

A fundamental event in the development and progression of malignant melanoma is the deregulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of tumor progression in melanoma and thus the most important member of the AP-1 transcription factor family for this disease. Interestingly, we revealed that c-Jun expression was regulated on the post-transcriptional level and therefore speculated that miRNAs could be involved in c-Jun regulation. We determined seed sequences for miR-125b and miR-527 in the coding region of c-Jun mRNA that hints at the direct involvement of miRNA-dependent regulation on the protein level. We found that the expression of miR-125b was significantly reduced in malignant melanoma cell lines and tissue samples compared with melanocytes, whereas miR-527 remained unchanged. In further functional experiments, treatment of melanoma cells with pre-miR-125b resulted in strong suppression of cellular proliferation and migration, supporting the role of miR-125b in melanoma. In addition, transfection of pre-miR-125b led to strong downregulation of c-Jun protein but not mRNA expression in melanoma cells. Luciferase assays using reporter plasmids containing the miR-125b seed sequence in the luciferase coding region confirmed the direct interaction with miR-125b. Furthermore, immunoprecipitation of Ago-2 revealed that c-Jun mRNA accumulated in the RNA-induced silencing complex after pre-miR-125b transfection in melanoma cells. In summary, we identified an important role for miR-125b in malignant melanoma. Moreover, we demonstrated post-transcriptional regulation of c-Jun by this miRNA and showed that c-Jun is a main mediator of the effects of miR-125b on melanoma cells.

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Acknowledgements

We would like to thank Lisa Ellmann for continuous assistance in cultivation. This work was supported by Melanoma Research Network of the Deutsche Krebshilfe e.V. (German Cancer Aid) and the DFG. GM is supported by grants from the Bavarian Ministry for education and science (BayGene), the European Union (ERC starting grant ‘sRNAs’, FP7 project ‘ONCOMIRs’) and the Bundesministerium für Bildung und Forschung (BMBF, NGFN+).

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Authors and Affiliations

  1. Institute of Pathology, University of Regensburg, Regensburg, Germany

    M Kappelmann, S Kuphal & A-K Bosserhoff

  2. Institute of Biochemistry, University of Regensburg, Regensburg, Germany

    G Meister

  3. Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel

    L Vardimon

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  1. M Kappelmann
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  2. S Kuphal
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Correspondence to A-K Bosserhoff.

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Kappelmann, M., Kuphal, S., Meister, G. et al. MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression. Oncogene 32, 2984–2991 (2013). https://doi.org/10.1038/onc.2012.307

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