Thomas, Gareth J; (2000) The role of αv integrins in regulating keratinocyte behaviour. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Integrins are a family of heterodimeric cell surface receptors involved in cell-cell and cell-matrix interactions. They consist of non-covalently linked α and β glycoprotein chains, and play an important role in regulating many aspects of cell behaviour including proliferation, differentiation and migration. The αv subunit is capable of dimerising with five β chains (β1, 3, 5, 6 and 8), but in normal oral epithelium is only expressed as αvβ5 (a vitronectin receptor). In wound healing and oral squamous cell carcinoma (SCC) however, expression of this integrin is downregulated and de novo expression of the αvβ6 dimer (a fibronectin receptor) is seen. The purpose of this study was to investigate the role of αvβ6 in modulating the behaviour of keratinocytes. Epithelial cell lines derived from an oral SCC were used. H357 is a cell line derived from a squamous cell carcinoma of the tongue and it lacks the αv subunit. H357 has been 'repaired' by transfection of the missing αv subunit to create V3 cells which predominantly express αvβ5 (and a low level of αvβ6). A cell line with high αvβ6 expression was created by using a retroviral construct to infect V3 cells with β6 cDNA (and also β3 cDNA as a control). Empty vector controls were also made. Introduction of β6 cDNA into the cells produced a functional fibronectin receptor and induced ligand-dependent upregulation of matrix metalloproteinase (MMP)-9 and -2. The upregulation could be blocked using a specific anti- αvβ6 blocking antibody. VB6 cells showed increased migration towards fibronectin compared to H357 and V3 cells. Migration towards collagen I did not differ between the cell lines. The capacity for terminal differentiation, as measured by involucrin expression (a precursor protein of the keratinocyte cornified envelope), was reduced in the VB6 cells. Introduction of the β6 subunit had no consistent effect on the growth rate of the cells on tissue culture plastic or in suspension. No cell line formed tumours in nude mice. High αvβ6 expression in the cell lines was associated with a less differentiated, more migratory phenotype and with increased secretion of MMP-9 and -2. High αvβ3 expression produced none of these effects. De novo expression of αvβ6 is seen in oral SCC and wound healing and these data suggest that αvβ6 may be pivotal in driving keratinocytes towards a more migratory phenotype.

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