The role of FOXM1 in oral squamous cell carcinoma
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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
Authors
Gemenetzidis, EmiliosCollections
- Theses [3824]