A62
MTBP as a prognostic indicator in squamous cell carcinoma of the head and neck (SCCHN)
Ashraf el-Fert1, Anna Behrendt1, Tim Helliwell1, Andy Dodson2, Andrew Jones1, Terence Jones1, Mark Boyd1
1University of Liverpool, Liverpool, UK, 2Royal Liverpool University Hospital, Liverpool, UK
Background
Mtbp was first identified as an Mdm2 binding protein that could alter cell cycle progression and contribute to p53 regulation in an MDM2-dependent manner. We have generated antibodies to Mtbp that enable us to examine Mtbp and MTBP in vitro and in vivo and have therefore examined MTBP regulation and expression in cells and in samples from patients with SCCHN.
Method
We have examined a cohort of 184 SCCHN patient samples on a tissue microarray by immunohistochemistry for p53, MDM2 and MTBP and have used standard statistical methods to analyse the data. The motility of SCCHN cell lines was measured in Boyden chambers and siRNA was used to modulate gene expression.
Results
p53 up-regulation in the presence of low levels of MDM2 is likely indicative of p53 mutation in patients with SCCHN and this phenotype defines a sub-set of patients with a reduced overall survival (P=0.035). However, loss of MTBP expression in these patients is associated with a significant further reduction in median survival from 32 to 14 months (P<0.0001). In addition we have found that MTBP knock-down with siRNA results in a significant reduction in motility in SCCHN cells.
Conclusion
Loss of MTBP appears to have a significant impact on patient overall survival in patients likely to harbour mutant p53 (phenotypically p53+ve, MDM2 ve). In vitro down-regulation of MTBP results in increased motility and thus we suggest that this loss of negative regulation of MTBP may be the cause of the association between loss of MTBP expression with reduced overall survival in patients with SCCHN. Further experiments will investigate the connection between this and p53 status in SCCHN cells.
