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Molecular Pathogenesis of Chronic Wounds: The Role of β‐Catenin and C‐MYC
Author(s) -
Stojadinovic O.,
Brem H.,
Lee B.,
Vouthounis C.,
Entero H.,
TomicCanic M.
Publication year - 2004
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1067-1927.2004.0abstracteg.x
Subject(s) - wound healing , keratinocyte , context (archaeology) , catenin , epidermis (zoology) , pathogenesis , carcinogenesis , cancer research , medicine , biology , pathology , immunology , wnt signaling pathway , microbiology and biotechnology , signal transduction , in vitro , cancer , anatomy , genetics , paleontology
The lack of understanding of molecular pathogenesis of impaired healing in chronic ulcers leads to a serious health issue that contributes to excessive limb amputations and mortality. Using biopsies from patients with chronic wounds, skin organ culture and primary keratinocytes in culture we identified that β‐catenin and its downstream target, c‐myc, play important role in development of chronic wounds. In contrast to normal epidermis, we observed significant nuclearization of β‐catenin and elevated c‐myc expression at the non‐healing wound edge of patients with chronic ulcers. In vitro studies indicated that activation and stabilization of nuclear β‐catenin inhibits wound healing and keratinocyte migration by: blocking EGF response and inducing c‐myc. Using Affymetrix large scale microarrays we found that β‐catenin downstream target, c‐myc, is induced in skin by an inhibitor of wound healing (glucocorticoids) and repressed in the initial phase of normal wound healing, 4 to 48 hr, whereas it becomes de‐repressed at 96 hr post wounding. Therefore, the activation of β‐catenin/c‐myc pathway(s) contributes to impaired healing by inhibiting of keratinocyte migration and altering keratinocyte differentiation. The presence of activated β‐catenin and c‐myc in the epidermis of chronic wounds may serve as molecular markers of impaired healing and future targets for therapeutic intervention. While β‐catenin signaling has been implicated in epithelial development and oncogenesis its role in wound healing has never been postulated. This further illustrates the importance of “tissue context” specificity, because β‐catenin in the context of malignant tissue promotes invasion whereas in the context of a wound environment does the opposite.