Evans, Richard D.; (2002) The effect of a squamous cell carcinoma associated β1 integrin mutation on cell behaviour. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Integrins are the main receptors for extracellular matrix proteins and are responsible for mediating attachment of most cell types to their surrounding matrix. In addition integrins regulate growth and differentiation of many cell types, including epidermal keratinocytes, through a variety of signalling pathways. Integrin loss or overexpression contributes to the pathogenesis of benign epidermal disorders and influences the incidence and prognosis of squamous cell carcinomas (SCC) and other tumours. However, no integrin mutations have yet been reported in tumours of any origin. In my thesis 1 have studied the SCC4 cell line isolated from a human oral SCC. This cell line has normal integrin expression and is poorly differentiated. When these cells are infected with a retrovirus encoding the wild-type chick βi integrin they regain the ability to differentiate. I found that these cells are heterozygous for a βi mutation, T1881, mapping to the A domain of the subunit. T1881 results in increased ligand binding, irrespective of the partner a subunit, both in solid phase assays with recombinant protein and in living cells. The mutation promotes cell attachment and spreading but not invasion or motility. It also alters integrin signalling as shown by increased levels of MAPK phosphorylation. When introduced into the SCC4 cell line the mutant βi integrin fails to stimulate differentiation. Activation of βi integrins in normal keratinocytes also suppresses differentiation. To discover how frequently similar mutations occur in SCC I screened 124 skin tumours for mutations in exons surrounding T188I. A single alanine to valine substitution was found in a single case. My results establish mutation as a mechanism by which integrins can contribute to tumour development and provide new insights into how integrins regulate keratinocyte differentiation.

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