TNF-alpha regulates epithelial expression of MMP-9 and integrin alphavbeta6 during tumour promotion. A role for TNF-alpha in keratinocyte migration?

Abstract

Mice deficient in TNF-alpha (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis and expression of MMP-9 is inhibited in TNF-alpha(-/-) mice during skin tumour development. In the early stages of tumour promotion, MMP-9 protein initially localized to the follicular epidermis but subsequently began to accumulate in the interfollicular epidermis of wild-type but not TNF-alpha(-/-) mice. Inhibition of TNF-alpha or MMP-9 function reduced keratinocyte migration in vitro. In addition, a deficiency of TNF-alpha delayed re-epithelialization in vivo and this correlated with reduced MMP-9 expression. Collectively, these data suggest that MMP-9 regulates keratinocyte migration in a TNF-alpha-dependent manner. Expression profiling of genes that control cell adhesion and migration revealed markedly lower levels of the integrin subunits alphav and beta6 in TNF-alpha(-/-) compared with wild-type keratinocytes in vitro. alphavbeta6 expression was upregulated by keratinocytes in vitro and during tumour promotion in vivo in a TNF-alpha-dependent manner. Furthermore, alphavbeta6 blockade significantly inhibited keratinocyte migration and TNF-alpha-stimulated MMP-9 expression in vitro. These data illustrate a novel TNF-alpha-dependent mechanism for the control of alphavbeta6 expression and suggest one pathway for TNF-alpha regulation of MMP-9. Increased MMP-9 and alphavbeta6 expression may stimulate epithelial cell migration during tumour formation and may be one mechanism whereby TNF-alpha acts as an endogenous tumour promoter.