The role of FOXM1 in oral squamous cell carcinoma

Abstract

FOXM1 transcription factor regulates the expression of a multitude of genes, which are important for cell proliferation, mitosis, and differentiation. Although it is abundantly expressed in majority of human solid tumours, its role in early stages of human neoplasia remains unclear. Oral squamous cell carcinoma (OSCC) is characterized by sequential genomic alterations, which lead to invasive malignancy. In this study, it is shown that FOXM1 is significantly upregulated in early oral pre-malignant and OSCC tissues and cultured keratinocytes. Furthermore, the current study suggests that FOXM1B is the main isoform driving the cell cycle dependent expression of FOXM1, and that it is expressed mainly at the G2 phase of human epithelial keratinocytes. In an attempt to understand why FOXM1 precedes epithelial malignancy, the present study investigated 1) the genomic profile of FOXM1B overexpressing human epithelial keratinocytes, and 2) whether FOXM1B overexpression interferes with the innate program of keratinocyte differentiation, which is frequently reported as being the earliest oncogenic event in epithelial neoplasia. First, by using a high-resolution Affymetrix single nucleotide polymorphism (SNP) mapping technique, this study provides the first evidence that FOXM1B overexpression alone in primay human keratinocytes was sufficient to induce genomic instability, mainly in the form of copy number alterations. FOXM1B overexpression also cooperated with damaging agents relevant to human epidermal (UVB) and oral epithelial cancer (Nicotine), to promote genomic instability in human keratinocytes. Second, by using a 3D-organotypic culture model of oral mucosa, sustained overexpression of FOXM1 was found to induce a hyper-proliferative phenotype with suprabasal proliferation, exhibiting perturbed markers of epithelial differentiation such as cytokeratin 13 and filaggrin, resembling early oral dysplastic epithelium. Based on these observations it is hypothesised that aberrant upregulation of FOXM1B serves as a ‘first hit’ whereby cells acquire genomic instability, and an abnormal differentiation program. The latter event promotes epithelial proliferation at the expense of terminal differentiation, allowing sufficient time for the accumulation of additional genetic aberrations/mutations required for tumour promotion and expansion. The Role of FOXM1 in Oral Squamous Cell Carcinoma