FKH domain-mediated nuclear FOXP3 suppresses gastric cancer malignancy via c-MYC/CDKN1A regulation, EMT inhibition,...

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Gastric cancer (GC) is a leading cause of cancer mortality globally, particularly in East Asia.
• The role of nuclear-localized full-length FOXP3 (FOXP3FL) in GC pathogenesis is under investigation.

Purpose of the Study:

• To investigate the function of nuclear FOXP3FL as an oncosuppressive factor in gastric cancer.
• To elucidate the molecular mechanisms underlying FOXP3FL's tumor-suppressive activity.

Main Methods:

• Analysis of FOXP3 expression levels in GC tissues and adjacent normal mucosa.
• In vitro and in vivo functional assays to assess the impact of FOXP3FL overexpression on GC cell behavior.
• Mechanistic studies involving gene expression analysis (MYC, CDKN1A, PTEN, PI3K-P110α) and signaling pathway evaluation (PI3K/AKT, EMT).

Main Results:

• Total FOXP3 was significantly reduced in GC tissues compared to normal mucosa.
• Nuclear FOXP3FL overexpression suppressed GC cell proliferation, migration, and invasion in vitro and in vivo.
• FOXP3FL repressed MYC transcription, induced CDKN1A, upregulated PTEN, downregulated PI3K-P110α, attenuated PI3K/AKT signaling, and impaired epithelial-mesenchymal transition (EMT).
• The forkhead (FKH) domain of FOXP3 is essential for its nuclear localization, transcriptional control, and antitumor activity.

Conclusions:

• Nuclear-localized FOXP3FL functions as a tumor suppressor in gastric cancer.
• The FKH domain is critical for FOXP3FL's oncosuppressive functions.
• FOXP3FL exerts its effects by regulating key genes involved in cell proliferation, metastasis, and signaling pathways like PI3K/AKT and EMT.