The Candidate Tumor Suppressor Gene Ecrg4 Inhibits Proliferation of the Inflammed Mucosal Epithelium

Abstract

Mucosal membranes play an important role in innate and adaptive immunity acting as physical and biological barriers that prevent and regulate the response to infections. Using whole‐genome gene arrays, we identified a small number of regulatory genes that are differentially expressed during otitis media (OM), a mucosal epithelial proliferative response to infection in the middle ear (ME). One such gene is Esophageal cancer related gene 4 (Ecrg4), a candidate tumor suppressor that we found is normally expressed in the quiescent ME. We found that Ecrg4 expression is strongly down‐regulated during the proliferative phase of infection but recovers as mucosal hyperplasia recedes. When tested in vitro, mucosal epithelial proliferation and migration was reduced by Ecrg4 over‐expression when hyper‐proliferating mucosal epithelial cells were harvested from infected ME. When the analogous experiment was performed in vivo, we observed a decrease in the thickness of the mucosal epithelial layer and a reduction in inflammatory infiltrate entering the ME cavity 48 hrs after infection. Together these data suggest that the down‐regulation of Ecrg4 gene expression after infection plays a determinant function in mucosal epithelial hyperplasia and are the first that point to the value of a therapeutic strategy targeting Ecrg4 in the inflammation‐immunity cascade that precipitates mucosal epithelial proliferation.