TFAP4 Regulation of MCM5 Activates the PI3K/AKT Pathway to Promote Invasion and Metastasis of Gastric Cancer.

[AIMS] To investigate the role of transcription factor activating enhancer-binding protein 4 (TFAP4) in gastric cancer (GC) progression and elucidate its mechanism in promoting metastasis and invasion through the PI3K/AKT signaling pathway.

[METHODS] Bioinformatics analysis was performed to assess TFAP4 expression in GC tissues. Clinical specimens were collected and validated for TFAP4 expression. Functional assays were conducted to evaluate the effects of TFAP4 overexpression and inhibition on GC cell proliferation, invasion, and metastasis. In vivo studies with HGC27 cells in BALB/c nude mice were used to assess tumor growth and metastasis. Mechanistic analysis included the measurement of MCM5 expression and activation of the PI3K/AKT signaling pathway, with PI3K inhibitor LY294002 and MCM5 knockdown applied to confirm the pathways involved.

[RESULTS] Elevated TFAP4 expression was observed in GC tissues, and its overexpression promoted GC cell proliferation, invasion, and metastasis. Conversely, TFAP4 inhibition suppressed these behaviors. In vivo studies confirmed that TFAP4 knockdown reduced tumor growth and metastasis in nude mice. Mechanistically, TFAP4 was found to activate MCM5, which in turn facilitated GC cell invasion and metastasis. Furthermore, TFAP4 and MCM5 activated the PI3K/AKT signaling pathway, as evidenced by increased p-PI3K and p-AKT expression. The effects of TFAP4 overexpression were reversed by MCM5 knockdown or treatment with the PI3K inhibitor LY294002.

[CONCLUSION] The TFAP4-MCM5 signaling axis promotes GC progression through the PI3K/AKT pathway, suggesting that targeting this axis could provide a potential therapeutic strategy for managing gastric cancer.