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

Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Taku Shigesawa, Gouki Kanbe, Megumi Kimura, Masaya Sugiyama, Masashi Mizokami, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Naoto Okubo, Shunsuke Ohnishi, Hiroshi Takeda, Naoya Sakamoto

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)372-380
Number of pages9
JournalCancer Biology and Therapy
Volume22
Issue number5-6
DOIs
Publication statusPublished - 2021
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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