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The EGF receptor ligand amphiregulin controls cell division via FoxM1

S W Stoll1, P E Stuart1, W R Swindell1

  • 1Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Oncogene
|August 4, 2015
PubMed

Insights

Silencing amphiregulin (AREG) in keratinocytes causes cell division failure and abnormal DNA content. Restoring forkhead box protein M1 (FoxM1) reverses these effects, revealing a new pathway for epithelial cancer treatment.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) signaling is crucial for epithelial cells and implicated in carcinomas.
  • Amphiregulin (AREG), an EGF-related factor, plays a role in epithelial cell function.

Purpose of the Study:

  • To investigate the role of AREG in keratinocyte proliferation and cell cycle progression.
  • To elucidate the molecular mechanisms underlying AREG's function in keratinocytes.

Main Methods:

  • Silencing of AREG using tetracycline-mediated RNA interference.
  • RNA-sequencing for transcriptome analysis.
  • Functional assays to assess cell proliferation, DNA content, and gene expression.

Main Results:

  • AREG silencing inhibited keratinocyte expansion, leading to mitotic failure and polyploidy (cells with ⩾ 4n DNA content).
  • Transcriptome analysis revealed significant gene expression changes upon AREG silencing, with some not rescued by EGF.
  • Downregulation of FoxM1 and its target genes preceded mitotic arrest, and FoxM1 re-expression rescued proliferation and DNA content abnormalities.

Conclusions:

  • AREG controls G2/M cell cycle progression and cytokinesis in keratinocytes through a FoxM1-dependent pathway.
  • This study identifies a novel AREG-FoxM1 axis in keratinocyte regulation.
  • The findings suggest potential therapeutic strategies targeting this pathway for epithelial cancers.

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