Involvement of N-terminally truncated variants of p73, ΔTAp73, in head and neck squamous cell cancer: A comparison with p53 mutations

Abstract

P73, a p53-related gene, encodes two classes of isoforms with opposing functions: 1) a full-length transactivation-competent p73 protein (TAp73) with tumour suppressor activity; and 2) a group of NH2-terminally truncated, transactivation-deficient p73 proteins, ΔEx2p73, ΔEx2-3p73, ΔNp73, and ΔN’p73 (collectively named ΔTAp73) with oncogenic activity. In this study, for the first time, we analyse the deregulations of TAp73 and ΔTAp73 in head and neck squamous cell cancer (HNSCC) and compare them to p53 status. We found that all the p73 isoforms in HNSCC tissue were up-regulated with respect to those in normal adjacent tissue. Concomitant up-regulations of p73 transcripts were often found in cancer tissue but not in normal tissue. p53 mutations and p73 transcript alterations are not mutually exclusive. All the HNSCC specimens studied had at least one p53 mutation and/or one ΔTAp73 transcript alteration. Although both the ΔNp73 and the TAp73 transcripts were found to be up-regulated in head and neck cancers, the predominant protein in the cancers analysed was ΔNp73. TAp73, in contrast, was only weakly expressed. This finding is highly relevant and sheds light on the puzzling question of the biological significance of TAp73 up-regulation in cancers. ΔNp73 protein levels were significantly overexpressed in HNSCC tissue compared to matched normal tissue (p=0.003). Furthermore, a trend was found for better overall survival in patients with a low expression of ΔNp73. Our results show that the deregulation of both the p53 and the p73 pathways plays an important role in inducing head and neck cancers.