title: Control of MicroRNA-21 expression in colorectal cancer cells by oncogenic epidermal growth factor/Ras signaling and Ets transcription factors.
abstract: MicroRNAs (miRs) are important regulators of gene expression in normal physiology and disease, and are widely misexpressed in cancer. A number of studies have identified miR-21 as an important promoter of oncogenesis. However, as is true of most miRs, the mechanisms behind the aberrant expression of miR-21 in cancer are poorly understood. Herein, we examine the regulation of miR-21 expression in colorectal cancer (CRC) cells by the oncogenic epidermal growth factor (EGF)/Ras pathway and by Ets transcription factors, modulators of epithelial oncogenesis that are frequently misexpressed in CRC. We show that EGF/Ras efficiently induces the miR-21 primary transcript, but this does not rapidly and simply translate into higher mature miR-21 levels. Rather, induction of mature miR-21 by constitutive activation of this pathway is slow, is associated with only minimal activation of mitogen-activated protein kinase, and may involve stimulation of post-transcriptional processing by mechanisms other than Dicer stabilization. We further identify Ets transcription factors as modifiers of miR-21 expression in CRC. The effects of Ets factors on miR-21 expression are cell context-dependent, and appear to involve both direct and indirect mechanisms. The Ets factor Pea3 emerges from our studies as a consistent repressor of miR-21 transcription. Overall, our studies identify a complex relationship between oncogenic pathways and steady-state miR-21 levels in CRC, and highlight the need for greater understanding of the control of miR expression in cancer and other disease states.
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Hanna B
authors.initials: HB
authors.lastname: Kern
authors.forename: Brian F
authors.initials: BF
authors.lastname: Niemeyer
authors.forename: Janet K
authors.initials: JK
authors.lastname: Parrish
authors.forename: Carol A
authors.initials: CA
authors.lastname: Kerr
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Yaghi
authors.forename: Jason D
authors.initials: JD
authors.lastname: Prescott
authors.forename: Arthur
authors.initials: A
authors.lastname: Gutierrez-Hartmann
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050783:Proto-Oncogene Proteins c-ets; D004815:Epidermal Growth Factor; D015689:Oncogene Protein p21(ras)