TY - JOUR
T1 - FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma
AU - Maehara, Osamu
AU - Suda, Goki
AU - Natsuizaka, Mitsuteru
AU - Shigesawa, Taku
AU - Kanbe, Gouki
AU - Kimura, Megumi
AU - Sugiyama, Masaya
AU - Mizokami, Masashi
AU - Nakai, Masato
AU - Sho, Takuya
AU - Morikawa, Kenichi
AU - Ogawa, Koji
AU - Ohashi, Shinya
AU - Kagawa, Shingo
AU - Kinugasa, Hideaki
AU - Naganuma, Seiji
AU - Okubo, Naoto
AU - Ohnishi, Shunsuke
AU - Takeda, Hiroshi
AU - Sakamoto, Naoya
N1 - Funding Information:
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].
Publisher Copyright:
© 2021 Taylor & Francis Group, LLC.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Cancer stem-like cells
KW - differentiation
KW - EMT
KW - esophageal squamous cell carcinoma
KW - FGFR
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U2 - 10.1080/15384047.2021.1939638
DO - 10.1080/15384047.2021.1939638
M3 - Article
C2 - 34224333
AN - SCOPUS:85109705200
SN - 1538-4047
VL - 22
SP - 372
EP - 380
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 5-6
ER -
