Alterations in epidermal biochemistry as a consequence of stage-specific genetic changes in skin carcinogenesis

Environ Health Perspect. 1991 Jun;93:3-10. doi: 10.1289/ehp.91933.


The induction of cancer on mouse skin by initiation-promotion protocols occurs through stages in which a benign squamous papilloma is an obligate precursor of squamous cell carcinoma. Activation of the Ha-ras gene is sufficient to produce the papilloma phenotype, while additional genetic changes are required for malignant conversion. The introduction of Ha-ras into normal keratinocytes suppresses the expression of differentiation markers, keratin K1 and K10, and loricrin (a cornified envelope precursor) and, to a lesser extent, filaggrin, at the level of transcription. However, cells initiated by Ha-ras express a nonepidermal keratin, K8. The transcription of K8 in these cells is sensitive to the level of medium Ca2+, being abundant in 0.5 mM Ca2+ and not detected in 0.05 mM Ca2+. Epidermal differentiation is regulated by signalling, which involves changes in phosphatidylinositol turnover and intracellular Ca2+. Cells initiated by Ha-ras do not differ from normal keratinocytes in their intracellular Ca2+ response patterns, at least in response to changes in extracellular Ca2+ and serum factors. However, c-Ha-ra keratinocytes have a high basal level of phosphatidylinositol (PI) turnover, which is additive with several other inducers of this pathway, including Ca2+ and aluminum fluoride. Additional studies suggest that high turnover of the PI pathway is incompatible with differentiation-specific gene expression in keratinocytes. We suggest this negative relationship is mediated through elevated diacylglycerol production and chronic down-modulation of protein kinase C. Protein kinase C is known to be essential for expression of differentiation-related genes in keratinocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Review

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • Calcium / metabolism
  • Carcinogens / pharmacology*
  • Carcinogens / toxicity
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / genetics*
  • Cells, Cultured
  • Epidermis / drug effects
  • Epidermis / metabolism*
  • Epidermis / pathology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, ras / drug effects*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Mice
  • Oncogene Protein p21(ras) / biosynthesis
  • Oncogene Protein p21(ras) / genetics*
  • Oncogene Protein p21(ras) / physiology
  • Oncogene Proteins v-fos / genetics*
  • Oncogene Proteins v-fos / physiology
  • Papilloma / chemically induced
  • Papilloma / genetics*
  • Papilloma / metabolism
  • Papilloma / pathology
  • Phenotype
  • Retroviridae
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Transduction, Genetic
  • Transfection


  • Biomarkers, Tumor
  • Carcinogens
  • Oncogene Proteins v-fos
  • Oncogene Protein p21(ras)
  • Calcium