Abstract
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Animals
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Base Sequence
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Binding Sites
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Proliferation
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology*
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Conserved Sequence / genetics
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Cyclin D / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Down-Regulation / genetics
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology*
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Evolution, Molecular
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Gene Expression Regulation, Neoplastic
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Humans
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / metabolism*
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Male
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Molecular Sequence Data
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Protein Binding / genetics
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S Phase / genetics
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Tumor Stem Cell Assay
Substances
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3' Untranslated Regions
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Cyclin D
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Cyclin-Dependent Kinase Inhibitor p21
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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MIRN7 microRNA, human
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MicroRNAs
Grants and funding
This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT) [grant numbers 155290 to L.P.-M. and 154542 to G.P.-A.], by the DGAPA-PAPIIT [grant numbers IN209212 L.P.-M. and IN227510 to G.P.-A.] and by a CONACyT Graduate Scholarship to K.F.M.-S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.