Activation of histamine H₄ receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non-metabolism signaling pathways.

Although dysregulation of histamine H₄ receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients. H4R activation not only significantly blocked cell proliferation, cell cycle, and invasion but also inhibited the growth of TE-2 xenografts and increased the survival of xenograft-bearing mice. According to the mechanistic experiments, both metabolism (acetyl-coenzyme A synthetase 2 (ACSS2))- and non-metabolism (mitogen-activated protein kinase (MAPK))-related pathways were involved in the effect of H4R activation on suppressing tumor proliferation and invasion. Based on these findings, H4R was overexpressed in esophageal cancer and exerted antitumor effects on ESCC proliferation and invasion, suggesting that H4R may be a novel potential target of therapies for ESCC. KEY function of H4R in ESCC and the underlying mechanisms were investigated. H4R expression was correlated with ESCC cell differentiation and patients' survival. Both metabolism (ACSS2) and non-metabolism (MAPK)-related pathways were involved. This study provided new insight into the relationship between H4R and ESCC. H4R may be a novel potential therapeutic target for ESCC.

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