EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis

J Exp Med. 2017 Oct 2;214(10):2889-2900. doi: 10.1084/jem.20170354. Epub 2017 Aug 21.

Abstract

Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal-regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention.

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Squamous Cell / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Epidermal Growth Factor / physiology*
  • Female
  • Follistatin-Related Proteins / physiology*
  • Genes, Switch / physiology
  • Head and Neck Neoplasms / metabolism
  • Immunoprecipitation
  • Mass Spectrometry
  • Mice, Inbred NOD
  • MicroRNAs / physiology*
  • Wound Healing / physiology*

Substances

  • Follistatin-Related Proteins
  • Fstl1 protein, mouse
  • MIRN198 microRNA, human
  • MIRN198 microRNA, mouse
  • MicroRNAs
  • Epidermal Growth Factor

Associated data

  • RefSeq/NM_003685
  • RefSeq/NM_005219