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

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 ne...

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Bibliographic Details
Published in:Oncotarget 2015-02, Vol.6 (5), p.2966-2980
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Autophagy
Cell Line, Tumor
Cell Movement
Disease Progression
Feedback, Physiological
Gene Expression Regulation, Neoplastic
Humans
Melanoma - genetics
Melanoma - metabolism
Melanoma - secondary
Mice, Inbred NOD
Mice, SCID
MicroRNAs - genetics
MicroRNAs - metabolism
Neoplasm Invasiveness
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Research Paper
RNA Interference
Signal Transduction
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
Time Factors
Transcription Factor AP-2 - genetics
Transcription Factor AP-2 - metabolism
Transfection
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.3070