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Title: The role of class B scavenger receptors in oral keratinocyte biology : implications for oral cancer metastasis
Author: Baidhani, Nibras Hamdan
ISNI:       0000 0004 6495 1091
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Scavenger receptors belong to a large receptor family that primarily bind lipid-containing molecules. Until recently, their expression has been described on macrophages and endothelial cells where their principal role is internalisation of lipoproteins and bacteria. However, to date, there is little evidence of scavenger receptor expression in the oral mucosa, therefore, this study aimed to determine functional expression of Class B scavenger receptors by oral keratinocytes. To achieve this, a panel of normal, dysplastic or cancerous oral keratinocytes from various oral sites were tested for the expression of class B scavenger receptor by qPCR, flow cytometry and by immunohistochemistry in patient biopsies. Internalisation of oxidised (ox) or acetylated (ac) low density lipoprotein (LDL), the main ligands for Class B scavenger receptors, was measured by immunofluorescence microscopy and flow cytometry, and receptor activation by immunoblotting for several intracellular signalling molecules. The effects of ox/ac-LDL on cell adhesion, invasion and migration as well as markers for epithelial to mesenchymal transition (EMT) were also measured in vitro. The results showed that class B scavenger receptor family members were expressed at the RNA and protein level by both normal and oral cancer cells with cancer cells expressing elevated levels. In addition, expression was markedly greater in oral cancer tissue than in normal oral mucosa. SCC4 cancer cells rapidly internalized ox/ac-LDL in a scavenger receptor-dependent manner that initiated phosphorylation of JNK. Stimulation with acLDL, and oxLDL in particular caused SCC4 cells to be less adherent, more invasive and display increased migration compared to controls. These cell functions were inhibited using fucoidan, a pan-class B scavenger receptor antagonist, or SP600125, a specific JNK inhibitor. In addition, oxLDL altered the expression of EMT markers driving oral cancer cells to a mesenchymal phenotype. These data suggest that class B scavenger receptors are up-regulated by oral cancer cells and that their activation by oxLDL pushes these cells to a more mesenchymal phenotype that significantly impacts on their ability to migrate, invade and therefore metastasise. These findings may have a significant impact on oral cancer.
Supervisor: Murdoch, Craig ; Colley, Helen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available