Abstract
MicroRNA profiling in isogenic models of cellular transformation involving either breast epithelial cells or fibroblasts reveals that expression of miR-193a is lower in transformed cells than in nontransformed cells. The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression during transformation. miR-193a inhibits cellular transformation by directly targeting the 3' untranslated regions of PLAU and K-Ras. Interestingly, miR-193a controls anchorage-independent growth in soft agar through K-Ras, whereas it affects invasive growth through PLAU. miR-193a overexpression inhibits the tumorigenicity of developmentally diverse but not all cancer cell types, and it inhibits tumor growth in colon- and breast-derived xenografts. Finally, expression of miR-193a is inversely correlated with PLAU and K-Ras in human colon adenocarcinomas. Thus, a pathway in which Max and RXRα inhibit miR-193a expression, thereby activating the PLAU and K-Ras oncogenes is important for distinct aspects of cellular transformation, as well as tumor growth and colon (and perhaps other types of) cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3' Untranslated Regions / genetics
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
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Breast / cytology
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Cell Line / metabolism
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Cell Line, Tumor / metabolism
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Cell Line, Tumor / pathology
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Cell Transformation, Neoplastic / genetics*
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Chromatin Immunoprecipitation
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Epithelial Cells / cytology
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Fibroblasts / cytology
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics*
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Genes, ras
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Genes, src
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Humans
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Mice
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Mice, Nude
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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Neoplasm Invasiveness / genetics
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Neoplasm Proteins / physiology*
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RNA, Small Interfering / pharmacology
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Random Allocation
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Retinoid X Receptor alpha
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Tumor Stem Cell Assay
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Urokinase-Type Plasminogen Activator / physiology*
Substances
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3' Untranslated Regions
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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MAX protein, human
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MIRN193 microRNA, human
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MicroRNAs
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Neoplasm Proteins
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RNA, Small Interfering
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Retinoid X Receptor alpha
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Urokinase-Type Plasminogen Activator