FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma

ABSTRACT

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial–mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.

KEYWORDS:

• Cancer stem-like cells
• FGFR
• EMT
• differentiation
• esophageal squamous cell carcinoma

Disclosure statement

No potential conflicts of interest were disclosed.

Supplementary materials

Supplemental data for this article can be accessed on the publisher’s website.

Abbreviations

CSCs	=	Cancer stem-like cells
DMEM	=	Dulbecco’s modified Eagle’s medium
DMSO	=	Dimethyl sulfoxide
EMT	=	Epithelial-mesenchymal transition
ESCC	=	Esophageal squamous cell carcinoma
FACS	=	Fluorescence activated cell sorting
FGF	=	Fibroblast growth factor
LDS	=	Lithium dodecyl sulfate
PBS	=	phosphate-buffered saline
SDS	=	Sodium dodecyl sulfate
TBS	=	Tris-buffered saline.
TCGA	=	The cancer genome atlas

Additional information

Funding

This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, KAKENHI [grant numbers 18K07959 to MN and 20K17039 to OM].