Transcriptional activation of EPHB1 by SOX2 promotes epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with an unfavorable prognosis, and the molecular mechanisms underlying its metastatic progression remain incompletely defined. Here, we investigated the functional role of ephrin type-B receptor 1 (EPHB1), a member of the ephrin receptor family, in ESCC metastasis. Integrated analyses of RNA-sequencing data and publicly available databases demonstrated that EPHB1 expression is significantly upregulated in ESCC tissues and is positively associated with advanced tumor grade and poor patient survival. Gain- and loss-of-function assays revealed that EPHB1 knockdown markedly inhibited ESCC cell migration, invasion, and epithelial-mesenchymal transition (EMT), whereas EPHB1 overexpression exerted the opposite effects. Consistently, in vivo metastasis assays further confirmed that EPHB1 promotes lung metastasis of ESCC cells. Mechanistically, we identified SRY-box transcription factor 2 (SOX2) as a critical upstream regulator that directly binds to the EPHB1 promoter and transcriptionally activates its expression. Rescue experiments demonstrated that SOX2-induced EMT and invasive capacity are largely mediated through EPHB1. Collectively, these findings uncover a previously unrecognized SOX2/EPHB1 signaling axis that drives ESCC metastasis and suggest EPHB1 as a potential therapeutic target for ESCC.