MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4

PLoS One. 2014 Sep 2;9(9):e103987. doi: 10.1371/journal.pone.0103987. eCollection 2014.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology*
  • Conserved Sequence / genetics
  • Cyclin D / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Down-Regulation / genetics
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology*
  • Evolution, Molecular
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Protein Binding / genetics
  • S Phase / genetics
  • Tumor Stem Cell Assay

Substances

  • 3' Untranslated Regions
  • Cyclin D
  • Cyclin-Dependent Kinase Inhibitor p21
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MIRN7 microRNA, human
  • MicroRNAs

Grant support

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.