Abstract 2594: Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells

Abstract

Abstract Alcohol drinking has been established as a major risk factor for esophageal diseases, such as gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). Certain mechanisms of alcohol-induced esophageal injury are supported by experimental data, whereas most are speculative or extrapolated from studies on cancers of other organ sites. Our previous study showed that ethanol exposure inhibited PAX9 expression in human esophageal squamous epithelial cells in vitro and in vivo, and promoted ESCC. In this study, we aimed to investigate the molecular pathways through which alcohol drinking suppresses PAX9 in esophageal squamous epithelial cells. Gene microarray, qRT-PCR, ChIP-PCR, Western blotting, and immunostaining were used to identify and validate inhibition of NOTCH-PAX9 signaling in human esophageal squamous epithelial cells and mouse esophagus after ethanol exposure. Human tissue samples were analyzed to further validate NOTCH inhibition by alcohol drinking. We first demonstrated the inhibition of NOTCH by ethanol exposure in vitro. NOTCH regulated PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. RBPJ and NOTCH intracellular domain (NICD1) ChIP-PCR confirmed Pax9 as a direct downstream target of NOTCH signaling in mouse esophagus. NOTCH inhibition by alcohol drinking was further validated in mouse esophagus and human tissue samples. In conclusion, ethanol exposure inhibited NOTCH signaling and thus suppressed PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. Our data support a novel mechanism of alcohol-induced esophageal injury through the inhibition of NOTCH-PAX9 signaling. As a result, chemical NOTCH activators may be used to prevent or treat alcohol-associated esophageal diseases such as GERD and ESCC. Citation Format: Zhaohui Xiong. Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2594.