Published in:
24-08-2021 | Metastasis | Original Article
Overexpression of FOXC1 Promotes Tumor Metastasis by Activating the Wnt/β-Catenin Signaling Pathway in Gastric Cancer
Published in: Digestive Diseases and Sciences | Issue 8/2022
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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 β-catenin. The in vivo effect of FOXC1 and β-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 β-catenin and transactivates β-catenin expression, which is responsible for the activation of EMT and metastasis in cells overexpressing FOXC1, while β-catenin knockdown can suppress the metastasis-induced by FOXC1.
Conclusions
FOXC1 promotes gastric cancer metastasis by activating Wnt/β-catenin signaling pathway, which may serve as a promising therapeutic target for gastric cancer treatment.