Suprabasal alpha6beta4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFbeta signalling.
Inappropriate alpha6beta4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of alpha6beta4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the beta4 cytoplasmic domain. Suprabasal alpha6beta4 also perturbed transforming growth factor beta (TGFbeta) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal alpha6beta4 relieved TGFbeta-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFbeta could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal alpha6beta4 promotes tumourigenesis by preventing TGFbeta from suppressing clonal expansion of initiated cells in the epidermal basal layer.
Owens
David M
DM
Keratinocyte Laboratory, CR-UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Romero
M Rosario
MR
Gardner
Clare
C
Watt
Fiona M
FM
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D039161:Integrin alpha6beta4 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015820:Cadherins; D002273:Carcinogens; D004268:DNA-Binding Proteins; D039161:Integrin alpha6beta4; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases