Upregulated forkhead‑box A3 elevates the expression of forkhead‑box A1 and forkhead‑box A2 to promote metastasis in esophageal cancer

Abstract

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.

Opposing Roles of FoxA1 and FoxA3 in Intrahepatic Cholangiocarcinoma Progression

“…High expression of FoxA3 was correlated with poor prognosis in lung cancer [16]. FoxA3 was also up-regulated and promoted metastasis in esophageal cancer cells through the regulations of FoxA1 and FoxA2 expressions [17]. These suggested that FoxA3 plays oncogenic function in lung cancer and esophageal cancer via elevation of FoxA1 and FoxA2 expressions.…”

“…High expressions of FoxA1 and FoxA3 in lung cancer were related with poor overall survival, whereas FoxA2 overexpression was associated with a better overall survival, suggesting the opposing roles between FoxA1/A3 and FoxA2 in the carcinogenesis [16]. FoxA1, FoxA2 and FoxA3 play synergistic roles in metastasis of esophageal cancer [17]. Expressions of estrogen receptors and EMT markers are induced along with CCA progression [18,19].…”

FoXA2 promotes esophageal squamous cell carcinoma progression by ZEB2 activation

“…In the present study, it was observed that FOXA2 was highly expressed in ESCC and its high expression was associated with TNM stage, distant metastasis, and relapse. In addition, FOXA2 was upregulated in esophageal adenocarcinoma and worked as a potential indicator in the tumor development [ 17 , 27 , 28 ]. These results were consistent with our findings that FOXA2 knockdown suppressed ESCC proliferation, migration, and invasion.…”

Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

“…In comparison, sparse data is available on the role of FoxA3 in cancer. One recent study demonstrated an increase in FoxA3 expression in esophageal cancer, which was associated with increased invasion, distant metastasis, disease stage, and a shorter overall survival ( 38 ). However, these TFs are correlated with oncogenic but also conversely tumor-suppressive functions (inhibiting metastasis) depending on how they interact with the transcriptional networks of tissue-specific cancers ( 29 , 39 , 40 ).…”