Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells
Autoři:
Asami Hotta Osada aff001; Kaori Endo aff001; Yujiro Kimura aff001; Kei Sakamoto aff004; Ryosuke Nakamura aff003; Kaname Sakamoto aff001; Koichiro Ueki aff002; Kunio Yoshizawa aff002; Keiji Miyazawa aff001; Masao Saitoh aff001
Působiště autorů:
Department of Biochemistry, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
aff001; Department of Oral and Maxillofacial Surgery, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
aff002; Center for Medical Education and Sciences, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
aff003; Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
aff004; Department of Oral Surgery, Kofu Municipal Hospital, Kofu, Yamanashi, Japan
aff005
Vyšlo v časopise:
PLoS ONE 14(11)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0217451
Souhrn
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.
Klíčová slova:
Phenotypes – Small interfering RNAs – Polymerase chain reaction – TGF-beta signaling cascade – Phosphorylation – Breast cancer – Squamous cell carcinomas – Fibroblast growth factor
Zdroje
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