Control of MicroRNA-21 expression in colorectal cancer cells by oncogenic epidermal growth factor/Ras signaling and Ets transcription factors

Document Type

Article

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.

Medical Subject Headings

Cell Line, Tumor; Colorectal Neoplasms (genetics, metabolism); Epidermal Growth Factor (metabolism); Gene Expression Regulation, Neoplastic; Humans; MicroRNAs (genetics, metabolism); Oncogene Protein p21(ras) (genetics, metabolism); Proto-Oncogene Proteins c-ets (metabolism); Signal Transduction; Transcription, Genetic

Publication Date

8-1-2012

Publication Title

DNA and cell biology

E-ISSN

1557-7430

Volume

31

Issue

8

First Page

1403

Last Page

11

PubMed ID

22553926

Digital Object Identifier (DOI)

10.1089/dna.2011.1469

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