Journal
ONCOTARGET
Volume 6, Issue 5, Pages 2966-2980Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3070
Keywords
Melanoma; metastasis; microRNA; p53 pathway; apoptosis
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Funding
- Deutsche Forschungsgemeinschaft [KU 1320/5-1, WO 991/4-1]
- German Federal Ministry of Research (BMBF) [0316175A]
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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 2a (TFAP2A/AP-2a) 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-2a.
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