Oncotarget

Research Papers:

miR-638 promotes melanoma metastasis and protects melanoma cells from apoptosis and autophagy

Animesh Bhattacharya _, Ulf Schmitz, Yvonne Raatz, Madeleine Schönherr, Tina Kottek, Marianne Schauer, Sandra Franz, Anja Saalbach, Ulf Anderegg, Olaf Wolkenhauer, Dirk Schadendorf, Jan C. Simon, Thomas Magin, Julio Vera, Manfred Kunz

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Oncotarget. 2015; 6:2966-2980. https://doi.org/10.18632/oncotarget.3070

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Abstract

Animesh Bhattacharya1, Ulf Schmitz2, Yvonne Raatz1, Madeleine Schönherr1, Tina Kottek1, Marianne Schauer1, Sandra Franz1, Anja Saalbach1, Ulf Anderegg1, Olaf Wolkenhauer2, Dirk Schadendorf3, Jan C. Simon1, Thomas Magin4, Julio Vera5 and Manfred Kunz1

1 Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig, Germany

2 Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany

3 Department of Dermatology, Venereology and Allergology, University Hospital Essen, Essen, Germany

4 Institute of Biology and Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany

5 Laboratory of Systems Tumor Immunology, Department of Dermatology, Faculty of Medicine, University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence:

Animesh Bhattacharya, email:

Keywords: Melanoma, metastasis, microRNA, p53 pathway, apoptosis

Received: September 25, 2014 Accepted: December 19, 2014 Published: December 26, 2014

Abstract

The present study identified miR-638 as one of the most significantly overexpressed miRNAs in metastatic lesions of melanomas compared with primary melanomas. miR-638 enhanced the tumorigenic properties of melanoma cells in vitro and lung colonization in vivo. mRNA expression profiling identified new candidate genes including TP53INP2 as miR-638 targets, the majority of which are involved in p53 signalling. Overexpression of TP53INP2 severely attenuated proliferative and invasive capacity of melanoma cells which was reversed by miR-638. Depletion of miR-638 stimulated expression of p53 and p53 downstream target genes and induced apoptosis and autophagy. miR-638 promoter analysis identified the miR-638 target transcription factor associated protein 2α (TFAP2A/AP-2α) as a direct negative regulator of miR-638, suggestive for a double-negative regulatory feedback loop. Taken together, miR-638 supports melanoma progression and suppresses p53-mediated apoptosis pathways, autophagy and expression of the transcriptional repressor TFAP2A/AP-2α.


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