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

// Animesh Bhattacharya 1 , Ulf Schmitz 2 , Yvonne Raatz 1 , Madeleine Schönherr 1 , Tina Kottek 1 , Marianne Schauer 1 , Sandra Franz 1 , Anja Saalbach 1 , Ulf Anderegg 1 , Olaf Wolkenhauer 2 , Dirk Schadendorf 3 , Jan C. Simon 1 , Thomas Magin 4 , Julio Vera 5 and Manfred Kunz 1 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.