Targeting the FOXA2-AGR2 axis overcomes cisplatin resistance in esophageal squamous cell carcinoma through inhibition of endoplasmic reticulum stress

Despite the oncogenic role of FOXA2 in esophageal squamous cell carcinoma (ESCC), its contribution to cisplatin (DDP) resistance remains unclear. This study aims to elucidate the underlying mechanisms. FOXA2 expression was evaluated in clinical sensitive and resistant ESCC tissues and cell lines. Overexpression and knockdown of FOXA2 were conducted in DDP-resistant EC109 cells (EC109/DDP), followed by assessment of proliferation, invasion, the half-maximal inhibitory concentration (IC 50 ) for DDP, and colony formation under DDP treatment. The effects of FOXA2/AGR2 axis on endoplasmic reticulum stress (ERS) and apoptosis was examined through rescue experiments. A xenograft mouse model injected with FOXA2-knockdown EC109/DDP cells was used to assess tumor growth and DDP response in vivo. FOXA2 was significantly upregulated in DDP-resistant ESCC tissues and cell lines. FOXA2 knockdown suppressed proliferation and invasion, reduced IC 50 for DDP, and promoted colony formation under DDP treatment in EC109/DDP cells. FOXA2 transcriptionally activated AGR2 expression in EC109/DDP cells. FOXA2 knockdown enhanced ERS, evidenced by increased IRE1α phosphorylation and XBP1 splicing, and promoted apoptosis. However, these effects were partially reversed by AGR2 overexpression. Furthermore, AGR2 overexpression reversed the inhibitory effects of FOXA2 knockdown on malignant behaviors and DDP resistance. Additionally, FOXA2 knockdown suppressed tumor growth and reversed DDP resistance in vivo. FOXA2 knockdown suppresses malignant behaviors and reverses DDP resistance in ESCC by transcriptionally suppressing AGR2. The FOXA2/AGR2 axis confers chemoresistance by attenuating pro-apoptotic ERS signaling, specifically the IRE1α-XBP1 pathway. Targeting this axis may represent a potential therapeutic avenue against cisplatin-resistant ESCC.