Overexpression of FOXC1 Promotes Tumor Metastasis by Activating the Wnt/β-Catenin Signaling Pathway in Gastric Cancer

Background Forkhead box protein C1 (FOXC1) is a transcription factor overexpressed in multiple cancers and is associated with poor prognosis. However, the function of FOXC1 in gastric cancer remains largely unknown. Aim This study aims to explore the role of FOXC1 in promoting gastric cancer metastasis. Methods FOXC1 expression in gastric cancer patients was measured using real-time PCR and western blot. The association of FOXC1 with patient survival was assessed using public dataset. Gastric cancer cells with FOXC1 overexpression or knockdown were established. Cell metastatic ability was assessed by the expression of epithelial-mesenchymal transition (EMT)-related genes (E-cadherin, N-cadherin, vimentin) and matrix metalloproteinase-9 (MMP-9) as well as by migration and invasion assays. Chromatin immunoprecipitation was used to evaluate the interaction between FOXC1 and beta-catenin. The in vivo effect of FOXC1 and beta-catenin was assessed in metastatic animal models. Results FOXC1 is overexpressed in gastric cancer and is associated with disease progression and poor patient survival. FOXC1 overexpression leads to the down-regulation of epithelial marker (E-cadherin) and the up-regulation of mesenchymal makers (N-cadherin, vimentin) and MMP-9, consistent with enhanced EMT. Moreover, cell migration and invasion are also activated, indicating increased metastatic ability. Notably, FOXC1 binds to the promoter region of beta-catenin and transactivates beta-catenin expression, which is responsible for the activation of EMT and metastasis in cells overexpressing FOXC1, while beta-catenin knockdown can suppress the metastasis-induced by FOXC1. Conclusions FOXC1 promotes gastric cancer metastasis by activating Wnt/beta-catenin signaling pathway, which may serve as a promising therapeutic target for gastric cancer treatment.