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Regulation of the urokinase-type plasminogen activation system in oral squamous carcinoma cell lines by the β6 integrin subunit

Dalvi, Nafisa; (2003) Regulation of the urokinase-type plasminogen activation system in oral squamous carcinoma cell lines by the β6 integrin subunit. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Over-expression of components of the urokinase system is well documented in cancer and is thought to enable tumour cells to migrate and invade. Changes in integrin expression are also a common feature of tumours and have been linked to changes in protease activity. The αv integrin family has been correlated with cancer progression; particularly the αvβ6 integrin is neo-expressed in a number of epithelial carcinomas and has been associated with metalloproteinase expression. Oral see keratinocytes, which had been transfected to express different integrin subunits, were used in this study. Cells expressing αvβ6 showed enhanced urokinase-type plasminogen activator (uPA) secretion compared to control cells. This was unaffected by plating on a variety of matrix ligands including fibronectin. However, cells over-expressing αvβ6 showed decreased urokinase receptor (uPAR) mRNA and protein expression, associated with decreased cell surface plasminogen activation. Therefore, uPAR levels and cell surface plasminogen activation were inversely related to αvβ6 expression. The up-regulation of uPA secretion and down-regulation of uPAR expression and function by the αvβ6 integrin was mediated through the unique 11 amino acid extension of the β6 cytoplasmic tail. Transfection of αvβ6 into melanoma cell lines did not affect the urokinase system, suggesting this is cell-specific. Morpholino antisense oligonucleotides targeted against the αv and β6 integrins and an inducible β6 gene expression system were also used in order to confirm effects of αvβ6 on the urokinase system. The roles of αvβ6 and uPA in cell migration and invasion were also investigated. Expression of αvβ6 into the keratinocytes promoted only fibronectin-dependent cell migration that was not uPA dependent but required plasmin activity. The dual regulation of the urokinase system by αvβ6 integrin suggests a complex system where levels of proteolysis in cancer invasion are precisely regulated.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Regulation of the urokinase-type plasminogen activation system in oral squamous carcinoma cell lines by the β6 integrin subunit
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Beta-integrin
URI: https://discovery.ucl.ac.uk/id/eprint/10104071
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