Loss of Grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin

PLoS One. 2014 Feb 20;9(2):e89247. doi: 10.1371/journal.pone.0089247. eCollection 2014.

Abstract

The Grainyhead-like 1 (GRHL1) transcription factor regulates the expression of desmosomal cadherin desmoglein 1 (Dsg1) in suprabasal layers of the epidermis. As a consequence, the epidermis of Grhl1-null mice displays fewer desmosomes that are abnormal in structure. These mice also exhibit mild chronic skin barrier defects as evidenced by altered keratinocyte terminal differentiation, increased expression of inflammatory markers and infiltration of the skin by immune cells. Exposure of Grhl1 (-/-) mice to a standard chemical skin carcinogenesis protocol results in development of fewer papillomas than in wild type control animals, but with a rate of conversion to squamous cell carcinoma (SCC) that is strikingly higher than in normal littermates. The underlying molecular mechanism differs from mice with conditional ablation of a closely related Grhl family member, Grhl3, in the skin, which develop SCC due to the loss of expression of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Carcinogens / toxicity
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology*
  • Cell Differentiation
  • Cell Membrane Permeability*
  • Cell Proliferation
  • Epidermis / metabolism
  • Epidermis / pathology*
  • Fluorescent Antibody Technique
  • Immunoenzyme Techniques
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Mice
  • Mice, Knockout
  • Papilloma / chemically induced
  • Papilloma / genetics
  • Papilloma / pathology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • Carcinogens
  • Grhl1 protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • 9,10-Dimethyl-1,2-benzanthracene