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- Title
TNF-aregulates epithelial expression of MMP-9 and integrinavß6 during tumour promotion. A role for TNF-ain keratinocyte migration?
- Authors
Scott, Kate A; Arnott, Caroline H; Robinson, Stephen C; Moore, Robert J; Thompson, Richard G; Marshall, John F; Balkwill, Frances R
- Abstract
Mice deficient in TNF-a(TNF-a-/- mice) are resistant to skin carcinogenesis and expression of MMP-9 is inhibited in TNF-a-/- 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-a-/- mice. Inhibition of TNF-aor MMP-9 function reduced keratinocyte migration in vitro. In addition, a deficiency of TNF-adelayed 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-a-dependent manner. Expression profiling of genes that control cell adhesion and migration revealed markedly lower levels of the integrin subunitsav andß6 in TNF-a-/- compared with wild-type keratinocytes in vitro.avß6 expression was upregulated by keratinocytes in vitro and during tumour promotion in vivo in a TNF-a-dependent manner. Furthermore,avß6 blockade significantly inhibited keratinocyte migration and TNF-a-stimulated MMP-9 expression in vitro. These data illustrate a novel TNF-a-dependent mechanism for the control ofavß6 expression and suggest one pathway for TNF-aregulation of MMP-9. Increased MMP-9 andavß6 expression may stimulate epithelial cell migration during tumour formation and may be one mechanism whereby TNF-aacts as an endogenous tumour promoter.Oncogene (2004) 23, 6954-6966. doi:10.1038/sj.onc.1207915 Published online 26 July 2004
- Subjects
EPITHELIUM; KERATINOCYTES; CELL adhesion; EPITHELIAL cells; CELL communication; REGENERATION (Biology)
- Publication
Oncogene, 2004, Vol 23, Issue 41, p6954
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207915