High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increases PI3K and MAPK signalling, cell migration and invasion

Br J Dermatol. 2014 Jun;170(6):1256-65. doi: 10.1111/bjd.12715.

Abstract

Background: Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist.

Objectives: To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells.

Methods: We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB.

Results: Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling.

Conclusions: Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Collagen Type VII / genetics
  • Collagen Type VII / metabolism*
  • Collagen Type VII / pharmacology
  • Epidermolysis Bullosa Dystrophica / enzymology*
  • Epidermolysis Bullosa Dystrophica / genetics
  • Epidermolysis Bullosa Dystrophica / pathology
  • Gene Knockdown Techniques / methods
  • Humans
  • Keratinocytes / enzymology
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / metabolism*
  • RNA, Small Interfering / pharmacology
  • Recombinant Proteins / pharmacology
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Transfection

Substances

  • COL7A1 protein, human
  • Collagen Type VII
  • RNA, Small Interfering
  • Recombinant Proteins
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinase Kinases