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<p>Background: Forkhead box M1 (FOXM1) has been identified as a key gene regulating immune escape in gastric cancer (GC). Therefore, elucidation of FOXM1-related molecular mechanisms may provide more information for immunotherapy of GC. Methods: The expression levels of FOXM1, methyltransferase like 3 (METTL3), and fibroblast growth factor receptor 4 (FGFR4) were analyzed using qRT-PCR and western blot. EdU assay, flow cytometry, transwell assay and sphere formation assay were used to assess cell proliferation, apoptosis, invasion and stemness. GC cells were co-cultured with phytohemagglutinin-stimulated PBMCs to measure the levels of immune-related factors by ELISA. CD8 + T cell apoptosis rate was analyzed by flow cytometry after co-cultured with GC cells. The interaction between FOXM1 and FGFR4/METTL3/IGF2BP2 was confirmed using ChIP assay, dual-luciferase reporter assay, MeRIP assay, RNA pull-down assay and RIP assay. Animal study was performed to explore the role of METTL3/FOXM1 <i>in vivo</i>. Results: FOXM1 expression was elevated in GC cells. FOXM1 knockdown promoted GC cell apoptosis and the levels of immune-related factors, while inhibiting cell proliferation, invasion, stemness and CD8 + T-cell apoptosis. FOXM1 bound to FGFR4 promoter to increase its transcription. FGFR4 overexpression reversed the promoting effect of FOXM1 knockdown on GC cell proliferation, invasion, stemness and immune escape. METTL3 could promote FOXM1 mRNA stability and expression by m6A modification, which was recognized by m6A reader IGF2BP2. METTL3 silencing suppressed GC cell proliferation, invasion, stemness and immune escape, while these effects were abolished by FOXM1 upregulation. In addition, interference of METTL3 reduced GC tumorigenesis by inhibiting FOXM1/FGFR4 axis. Conclusion: METTL3/FOXM1/FGFR4 is a key regulatory axis in regulating GC progression and immune escape, which may provide potential molecular targets for immunotherapy of GC.</p>

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METTL3-Modified FOXM1 Promotes Proliferation, Invasion, Stemness, and Immune Escape of Gastric Cancer by Influencing the Transcription of FGFR4

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Pengqing Jiao,
  • Ming Liu,
  • Hongfang Ma,
  • Shuying Zhang,
  • Zhongkai Wang

摘要

Background: Forkhead box M1 (FOXM1) has been identified as a key gene regulating immune escape in gastric cancer (GC). Therefore, elucidation of FOXM1-related molecular mechanisms may provide more information for immunotherapy of GC. Methods: The expression levels of FOXM1, methyltransferase like 3 (METTL3), and fibroblast growth factor receptor 4 (FGFR4) were analyzed using qRT-PCR and western blot. EdU assay, flow cytometry, transwell assay and sphere formation assay were used to assess cell proliferation, apoptosis, invasion and stemness. GC cells were co-cultured with phytohemagglutinin-stimulated PBMCs to measure the levels of immune-related factors by ELISA. CD8 + T cell apoptosis rate was analyzed by flow cytometry after co-cultured with GC cells. The interaction between FOXM1 and FGFR4/METTL3/IGF2BP2 was confirmed using ChIP assay, dual-luciferase reporter assay, MeRIP assay, RNA pull-down assay and RIP assay. Animal study was performed to explore the role of METTL3/FOXM1 in vivo. Results: FOXM1 expression was elevated in GC cells. FOXM1 knockdown promoted GC cell apoptosis and the levels of immune-related factors, while inhibiting cell proliferation, invasion, stemness and CD8 + T-cell apoptosis. FOXM1 bound to FGFR4 promoter to increase its transcription. FGFR4 overexpression reversed the promoting effect of FOXM1 knockdown on GC cell proliferation, invasion, stemness and immune escape. METTL3 could promote FOXM1 mRNA stability and expression by m6A modification, which was recognized by m6A reader IGF2BP2. METTL3 silencing suppressed GC cell proliferation, invasion, stemness and immune escape, while these effects were abolished by FOXM1 upregulation. In addition, interference of METTL3 reduced GC tumorigenesis by inhibiting FOXM1/FGFR4 axis. Conclusion: METTL3/FOXM1/FGFR4 is a key regulatory axis in regulating GC progression and immune escape, which may provide potential molecular targets for immunotherapy of GC.