@article{10.1371/journal.pone.0217451, doi = {10.1371/journal.pone.0217451}, author = {Osada, Asami Hotta AND Endo, Kaori AND Kimura, Yujiro AND Sakamoto, Kei AND Nakamura, Ryosuke AND Sakamoto, Kaname AND Ueki, Koichiro AND Yoshizawa, Kunio AND Miyazawa, Keiji AND Saitoh, Masao}, journal = {PLOS ONE}, publisher = {Public Library of Science}, title = {Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells}, year = {2019}, month = {11}, volume = {14}, url = {https://doi.org/10.1371/journal.pone.0217451}, pages = {1-16}, 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.}, number = {11}, }