Abstract
The epithelial–mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. ZEB1/2 are EMT transcription factors that are positively correlated with EMT phenotypes and breast cancer aggressiveness. ZEB1/2 regulate the alternative splicing and hence isoform switching of fibroblast growth factor receptors (FGFRs) by repressing the epithelial splicing regulatory proteins, ESRP1 and ESRP2. Here, we show that the mesenchymal-like phenotypes of oral squamous cell carcinoma (OSCC) cells are dependent on autocrine FGF–FGFR signaling. Mesenchymal-like OSCC cells express low levels of ESRP1/2 and high levels of ZEB1/2, resulting in constitutive expression of the IIIc-isoform of FGFR, FGFR(IIIc). By contrast, epithelial-like OSCC cells showed opposite expression profiles for these proteins and constitutive expression of the IIIb-isoform of FGFR2, FGFR2(IIIb). Importantly, ERK1/2 was constitutively phosphorylated through FGFR1(IIIc), which was activated by factors secreted autonomously by mesenchymal-like OSCC cells and involved in sustained high-level expression of ZEB1. Antagonizing FGFR1 with either inhibitors or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits. Therefore, autocrine FGF–FGFR(IIIc) signaling appears to be responsible for sustaining ZEB1/2 at high levels and the EMT phenotype in OSCC cells.
Highlights
Oral tongue squamous cell carcinoma (OSCC) is one of the most common malignancies in head and neck cancers[1]
In the study we found that, similar to the basal-like subtype of breast cancer, OSCC cells with high levels of ZEB1/2 and low levels of E-cadherin and ESRP1/2 exhibited mesenchymal-like traits with fibroblast growth factor receptor (FGFR)(IIIc) isoforms
During transforming growth factor-β (TGF-β)–induced epithelial–mesenchymal transition (EMT) in NMuMG cells, TGF-β induces ZEB1/2 expression while repressing ESRP1/2 expression, leading to isoform switching from FGFR2(IIIb) to FGFR1 (IIIc), but not to FGFR2(IIIc)[6, 17]
Summary
Oral tongue squamous cell carcinoma (OSCC) is one of the most common malignancies in head and neck cancers[1]. Most patients on their first visit to hospitals are diagnosed with locoregional initial symptoms of the disease. The process of cancer cell invasion involves the loss of cell–cell interactions along with the acquisition of motility, and is partly associated with the epithelial–mesenchymal transition (EMT)[3]. The levels of ZEB1/2 in particular correlate positively with EMT phenotypes and the aggressiveness of breast cancer cells[6, 7]. Why expression of ZEB1/2 is sustained at high levels in aggressive cancer cells
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