Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells.
Alternative Splicing
/ genetics
Animals
Carcinoma, Squamous Cell
/ genetics
Cell Line, Tumor
Epithelial Cells
/ physiology
Epithelial-Mesenchymal Transition
/ genetics
Fibroblast Growth Factors
/ genetics
Humans
MAP Kinase Signaling System
/ genetics
Mice
Mouth Neoplasms
/ genetics
Phenotype
Phosphorylation
/ genetics
Protein Isoforms
/ genetics
RNA, Small Interfering
/ genetics
Receptors, Fibroblast Growth Factor
/ genetics
Signal Transduction
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
09
05
2019
accepted:
17
09
2019
entrez:
5
11
2019
pubmed:
5
11
2019
medline:
14
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31682640
doi: 10.1371/journal.pone.0217451
pii: PONE-D-19-13214
pmc: PMC6827898
doi:
Substances chimiques
Protein Isoforms
0
RNA, Small Interfering
0
Receptors, Fibroblast Growth Factor
0
Fibroblast Growth Factors
62031-54-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0217451Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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