ARSENIC INDUCES OVEREXPRESSION OF GROWTH-FACTORS IN HUMAN KERATINOCYTES

Although epidemiological studies have shown that inorganic arsenicals are human skin carcinogens and induce hyperproliferation and hyperkera tosis, there is currently no known mechanism for their action or an es tablished animal model for its study. We observed increased mRNA trans cripts and secretion of keratinocyte growth factors, including granulo cyte macrophage-colony stimulating factor (GM-CSF) and transforming gr owth factor-alpha (TGF alpha) and the proinflammatory cytokine tumor n ecrosis factor-alpha in primary human epidermal keratinocytes cultured in the presence of low micromolar concentrations of sodium arsenite. Treatment with sodium arsenite resulted in a significant increase in c ell proliferation, as indicated by increases in cell numbers, c-myc ge ne expression, and incorporation of [H-3]thymidine into cellular DNA. Studies of transcriptional regulation indicate that the rate of GMCSF mRNA transcription is increased, while the elevated TGF alpha is likel y the result of message stabilization, While a number of cytokine regu latory networks exist in the skin, studies utilizing neutralizing anti bodies against the growth factors of interest indicate that inhibition of the arsenic-induced increase in TGF alpha results in a correspondi ng decrease in the gene expression and secretion of CM-CSF. The presen t studies demonstrate that growth-promoting cytokines and growth facto rs are induced in keratinocytes following treatment with arsenic and c ould play a significant role in arsenic-induced skin cancer. (C) 1996 Academic Press, Inc.