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

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

Journal

Oncotarget

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Volume

6

ISBN/ISSN

1949-2553

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Pages Count

15

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Impact Journals

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DOI

10.18632/oncotarget.3070