title: Inhibition of miR-193a expression by Max and RXRα activates K-Ras and PLAU to mediate distinct aspects of cellular transformation.
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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Asaf
authors.initials: A
authors.lastname: Rotem
authors.forename: Kevin
authors.initials: K
authors.lastname: Struhl
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D001940:Breast / Q000166:cytology; D002460:Cell Line / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D011905:Genes, ras; D016391:Genes, src; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011897:Random Allocation; D047490:Retinoid X Receptor alpha; D014410:Tumor Stem Cell Assay; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D014568:Urokinase-Type Plasminogen Activator