Dr. Germolec et al., ARSENIC INDUCES OVEREXPRESSION OF GROWTH-FACTORS IN HUMAN KERATINOCYTES, Toxicology and applied pharmacology, 141(1), 1996, pp. 308-318
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.