Evaluation of the role of EGFR, SOX2 and PAX9 in oral carcinogenesis

Abstract

Oral squamous cell carcinoma (OSCC) is a major global healthcare problem. OSCC has devastating consequences for many patients diagnosed with the disease. Outcomes may be improved if the disease is identified in its precursor stages, termed oral potentially malignant disorders (OPMD). Unfortunately, histological assessment of OPMD does not reliably predict which cases will progress to OSCC. Several candidate biomarkers have emerged in recent decades. To date, however, none have been validated for use in clinical practice. This study sought to address the continuing need for biomarkers that stratify OPMD according to their risk of malignant transformation. Our data show that EGFR gene copy number abnormalities correlate with malignant transformation in OPMD. EGFR genomic gain was also present in a quarter of early-stage OSCC. SOX2 had a heterogeneous expression profile in both OPMD and OSCC, limiting its clinical utility. Nevertheless, the pattern of SOX2 expression suggests it may be a marker of OSCC stem cells and consequently represent a potential chemotherapeutic target. PAX9 is down-regulated in OPMD and early-stage OSCC. Following a course of chemical induction, Pax9-deficient mice were more likely to develop OPMD and OSCC than controls. These findings support the hypothesis that PAX9 has a tumour-suppressor function. In addition to enhanced local sensitivity to chemical induction, Pax9-deficient mice were more susceptible to the toxic systemic effects of treatment. A modified protocol for chemical induction in Pax9-deficient mice is recommended. Paradoxically, our analysis of human tissues showed increased PAX9 expression in OPMD that underwent malignant transformation, suggesting that, in some circumstances, PAX9 may have a tumour-promoting effect. Finally, we summarise the generation of stably transfected cell lines in which PAX9 and SOX2 expression may be manipulated by tetracycline administration. These cell lines will facilitate future studies of the functional role of PAX9 and SOX2 in oral carcinogenesis.