Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in...

Esophageal cancer (EC) is one of the most lethal cancers currently known. Members of the forkhead-box A (FOXA) family, including FOXA1 and FOXA2, have been reported to regulate EC progression. However, the role of FOXA3, which is another FOXA member, has not yet been investigated. In the present study, public dataset analyses and immunohistochemistry of 96 samples from patients with EC were performed to determine the potential roles of FOXA3 in EC. The results revealed that FOXA3 was significantly upregulated in EC tumor tissues and Barrett's esophagus tissues. In addition, FOXA3 upregulation was positively associated with tumor invasion, distant metastasis, tumor-node-metastasis stage and shorter overall survival in patients with EC, and multivariate analysis identified FOXA3 as an independent prognostic marker. In vitro experiments demonstrated that the migratory and invasive abilities of EC109 and EC9706 cell lines were inhibited following FOXA3 knockdown. Notably, FOXA3 expression levels were positively correlated with FOXA1 and FOXA2 expression levels according to The Cancer Genome Atlas dataset analysis. Furthermore, FOXA3 knockdown decreased the expression levels of FOXA1 and FOXA2 in EC109 and EC9706 cell lines. Conversely, FOXA1 or FOXA2 overexpression compensated for the effects of FOXA3 knockdown on the migratory and invasive capacities of EC cells. In conclusion, the present study demonstrated that FOXA3 upregulation in EC cells promoted metastasis through regulation of other FOXA members.