Abstract
Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine / metabolism*
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Adenosine Deaminase / genetics
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Adenosine Deaminase / metabolism
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Animals
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Base Sequence
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Cell Line, Tumor
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic*
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Genes, Reporter
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Humans
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Inosine / metabolism*
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Luciferases / genetics
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Luciferases / metabolism
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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MicroRNAs
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Molecular Sequence Data
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Neoplasm Metastasis
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Neoplasm Transplantation
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RNA Editing*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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mRNA Cleavage and Polyadenylation Factors / genetics
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mRNA Cleavage and Polyadenylation Factors / metabolism
Substances
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CPEB1 protein, human
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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MIRN455 microRNA, human
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MicroRNAs
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RNA-Binding Proteins
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Transcription Factors
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mRNA Cleavage and Polyadenylation Factors
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Inosine
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Luciferases
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ADAR protein, human
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Adenosine Deaminase
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Adenosine