Alcohol exposure promotes MMP9-mediated CCN1 cleavage in esophageal adenocarcinoma

Background: Alcohol consumption has been a risk factor for more than 200 diseases, including esophageal cancer. CCN1, a matricellular protein, is highly expressed in esophageal squamous cell carcinoma (ESCC) but is barely detectable in esophageal adenocarcinoma (EAC). Alcohol consumption has been identified as a major contributor to ESCC development, but its role in EAC is uncertain. This study investigates how alcohol exposure affects CCN1 expression and function in esophageal epithelial cells. Methods: CCN1 expression in rat esophagus was assessed after 4 weeks of alcohol consumption. Esophageal cell lines, including normal and tumor, were exposed to alcohol to simulate the in vivo experiments. Results: Alcohol exposure moderately increased CCN1 expression in both normal and tumor cells but significantly increased CCN1 cleavage in EAC cells only, generating an 18 kDa fragment benefiting tumor growth. MMP9, which was active in EAC cells exclusively, was found to mediate this cleavage. Forced activation of MMP9 in either normal or ESCC cells improved cell viability while inhibition of MMP9 in EAC cells attenuated cell survival. Conclusions: Alcohol exposure promotes MMP9-mediated CCN1 cleavage in EAC cells, turning CCN1 from an EAC antagonist to an EAC agonist.