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

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 i...

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Bibliographic Details
Published in:Cancer biology & therapy 2021-06, Vol.22 (5-6), p.372-380
Main Authors: Maehara, Osamu, Suda, Goki, Natsuizaka, Mitsuteru, Shigesawa, Taku, Kanbe, Gouki, Kimura, Megumi, Sugiyama, Masaya, Mizokami, Masashi, Nakai, Masato, Sho, Takuya, Morikawa, Kenichi, Ogawa, Koji, Ohashi, Shinya, Kagawa, Shingo, Kinugasa, Hideaki, Naganuma, Seiji, Okubo, Naoto, Ohnishi, Shunsuke, Takeda, Hiroshi, Sakamoto, Naoya
Format: Article
Language:English
Subjects:
Cancer stem-like cells
Carcinoma, Squamous Cell - genetics
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
differentiation
EMT
Epithelial-Mesenchymal Transition
Esophageal Neoplasms - genetics
esophageal squamous cell carcinoma
Esophageal Squamous Cell Carcinoma - genetics
FGFR
Gene Expression Regulation, Neoplastic
Humans
Proto-Oncogene Proteins c-akt
Receptor, Fibroblast Growth Factor, Type 2 - genetics
Research Paper
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Summary: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.
ISSN:1538-4047
1555-8576
DOI:10.1080/15384047.2021.1939638