TNF- alpha regulates epithelial expression of MMP-9 and integrin alpha v beta 6 during tumour promotion. A role for TNF- alpha in keratinocyte migration?

• Published in: Oncogene Vol. 23; no. 41; pp. 6954 - 6966
• Main Authors: Scott, KA, Arnott, CH, Robinson, S C, Moore, R J, Thompson, R G, Marshall, J F, Balkwill, FR
• Format: Journal Article
• Language: English
• Published: 09.09.2004
• ISSN: 0950-9232
• DOI: 10.1038/sj.onc.1207915

Mice deficient in TNF- alpha (TNF- alpha super(-/-) mice) are resistant to skin carcinogenesis and expression of MMP-9 is inhibited in TNF- alpha super(-/-) 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 super(-/-) 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 alpha v and beta 6 in TNF- alpha super(-/-) compared with wild-type keratinocytes in vitro. alpha v beta 6 expression was upregulated by keratinocytes in vitro and during tumour promotion in vivo in a TNF- alpha -dependent manner. Furthermore, alpha v beta 6 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 alpha v beta 6 expression and suggest one pathway for TNF- alpha regulation of MMP-9. Increased MMP-9 and alpha v beta 6 expression may stimulate epithelial cell migration during tumour formation and may be one mechanism whereby TNF- alpha acts as an endogenous tumour promoter.