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
doi: 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:

Breast cancer – Fibroblast growth factor – Phenotypes – Phosphorylation – Polymerase chain reaction – Small interfering RNAs – Squamous cell carcinomas – TGF-beta signaling cascade


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