Functional analyses of FGFR1(IIIc) in oral squamous cell carcinoma cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K18691
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: University of Yamanashi
• Principal Investigator: Hotta Asami 山梨大学, 医学部附属病院, 医員 (00754607)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: FGFR1c isoform / EMT / ZEB1/2 / FGF2 / 口腔扁平上皮癌 / CSC

Outline of Final Research Achievements

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, ERK 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 an inhibitor or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits.

Free Research Field

口腔扁平上皮癌

Academic Significance and Societal Importance of the Research Achievements

最近FGFRとN-cadherinの結合は双方の膜上の安定性を高めN-cadherinへの接着を増強させ運動性を抑制する事が報告された。間質内を模倣しているとはいえないが、FGFR1IIIc とN-cadherinの相互作用によってあらたなシグナルが構築されている可能性は高い。また膀胱癌及び結腸癌においてE-cadherinが減少したFGFR2IIIbの発現低下が悪性形質に貢献していることが報告された。IIIbが上皮細胞特異的なE-cadherinと結合しEMTを抑制し逆にMETを誘導するようなシグナルを伝達しているとするとこのような会合を制御するような分子も将来治療薬として有用かもしれない。