TNF-alpha regulates epithelial expression of MMP-9 and integrin alphavbeta6 during tumour promotion. A role for TNF-alpha in keratinocyte migration?
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.
Translational Oncology Laboratory, Cancer Research UK Cancer Centre, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Kate A
KA
Scott
Caroline H
CH
Arnott
Stephen C
SC
Robinson
Robert J
RJ
Moore
Richard G
RG
Thompson
John F
JF
Marshall
Frances R
FR
Balkwill
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D002465:Cell Movement; D004817:Epidermis / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016023:Integrins / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D012878:Skin Neoplasms / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014945:Wound Healing
D000951:Antigens, Neoplasm; D016023:Integrins; D012333:RNA, Messenger; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; C073878:integrin alphavbeta6; D020780:Matrix Metalloproteinase 9