AUTHOR=Yang Chengcheng , Song Dingli , Zhao Fengyu , Wu Jie , Zhang Boxiang , Ren Hong , Sun Qi , Qin Sida 

TITLE=Comprehensive analysis of the prognostic value and immune infiltration of FGFR family members in gastric cancer

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.936952

DOI=10.3389/fonc.2022.936952

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Fibroblast growth factor receptors (<italic>FGFRs</italic>) modulate numerous cellular processes in tumor cells and tumor microenvironment. However, the effect of <italic>FGFRs</italic> on tumor prognosis and tumor-infiltrating lymphocytes in gastric cancer (GC) remains controversial.</p></sec><sec><title>Methods</title><p>The expression of four different types of <italic>FGFRs</italic> was analyzed <italic>via</italic> GEPIA, TCGA-STAD, and GTEX databases and our 27 pairs of GC tumor samples and the adjacent normal tissue. Furthermore, the Kaplan–Meier plot and the TCGA database were utilized to assess the association of FGFRs with clinical prognosis. The R software was used to evaluate <italic>FGFRs</italic> co-expression genes with GO/KEGG Pathway Enrichment Analysis. <italic>In vitro</italic> and <italic>in vivo</italic> functional analyses and immunoblotting were performed to verify <italic>FGFR4</italic> overexpression consequence. Moreover, the correlation between <italic>FGFRs</italic> and cancer immune infiltrates was analyzed by TIMER and TCGA databases. And the efficacy of anti-PD-1 mAb treatment was examined in NOG mouse models with overexpressed <italic>FGFR1</italic> or <italic>FGFR4</italic>.</p></sec><sec><title>Results</title><p>The expression of <italic>FGFRs</italic> was considerably elevated in STAD than in the normal gastric tissues and was significantly correlated with poor OS and PFS. ROC curve showed the accuracy of the <italic>FGFRs</italic> in tumor diagnosis, among which <italic>FGFR4</italic> had the highest ROC value. Besides, univariate and multivariate analysis revealed that <italic>FGFR4</italic> was an independent prognostic factor for GC patients. According to a GO/KEGG analysis, the FGFRs were implicated in the ERK/MAPK, PI3K-AKT and extracellular matrix (ECM) receptor signaling pathways. <italic>In vivo</italic> and <italic>in vitro</italic> studies revealed that overexpression of FGFR4 stimulated GC cell proliferation, invasion, and migration. In addition, <italic>FGFR1</italic> expression was positively correlated with infiltrating levels of CD8+ T-cells, CD4+ T-cells, macrophages, and dendritic cells in STAD. In contrast, <italic>FGFR4</italic> expression was negatively correlated with tumor-infiltrating lymphocytes. Interestingly, overexpression of <italic>FGFR1</italic> in the NOG mouse model improved the immunotherapeutic impact of GC, while overexpression of <italic>FGFR4</italic> impaired the effect. When combined with an <italic>FGFR4</italic> inhibitor, the anti-tumor effect of anti-PD-1 treatment increased significantly in a GC xenograft mouse model with overexpressed <italic>FGFR4.</italic></p></sec><sec><title>Conclusions</title><p><italic>FGFRs</italic> has critical function in GC and associated with immune cell infiltration, which might be a potential prognosis biomarker and predictor of response to immunotherapy in GC.</p></sec>