Molecular Pathogenesis of Chronic Wounds: The Role of Beta-Catenin and C-Myc in the Inhibition of Epithelialization and Wound Healing

Am J Pathol. 2005 Jul;167(1):59-69. doi: 10.1016/s0002-9440(10)62953-7.

Abstract

Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic ulcers is a serious health issue that contributes to excessive limb amputations and mortality. Here we show that beta-catenin and its downstream targets in keratinocytes, c-myc, and keratins K6 and K16, play important roles in the development of chronic wounds. In contrast to normal epidermis, we observed a significant nuclear presence of beta-catenin and elevated c-myc expression at the nonhealing wound edge of chronic ulcers from 10 patients. In vitro studies indicated that stabilization of nuclear beta-catenin inhibited wound healing and keratinocyte migration by blocking epidermal growth factor response, inducing c-myc and repressing the K6/K16 keratins (cytoskeletal components important for migration). The molecular mechanism of K6/K16 repression involved beta-catenin and arginine methyltransferase (CARM-1) acting as co-repressors of glucocorticoid receptor monomers. We conclude that activation of the beta-catenin/c-myc pathway(s) contributes to impaired healing by inhibiting keratinocyte migration and altering their differentiation. The presence of activated beta-catenin and c-myc in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biomarkers / metabolism*
  • Blotting, Northern
  • Cell Differentiation / physiology
  • Cell Movement / physiology
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism*
  • Epidermal Cells
  • Epidermal Growth Factor / metabolism
  • Epidermis / physiology
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins
  • Keratinocytes / cytology*
  • Keratins / metabolism
  • Methyltransferases / metabolism
  • Protein-Arginine N-Methyltransferases
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Trans-Activators / metabolism*
  • Transfection
  • Wound Healing / physiology*
  • beta Catenin

Substances

  • Biomarkers
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Trans-Activators
  • beta Catenin
  • Epidermal Growth Factor
  • Keratins
  • Methyltransferases
  • PRMT2 protein, human
  • Protein-Arginine N-Methyltransferases