SMAD4 and infectious otitis media: Given that SMAD4 protein levels and phosphorylated levels of SMAD2 and SMAD3 were significantly downregulated in the colonic epithelium of Htr2bΔIEC mice treated with AOM/DSS (Figures 2F, G, and S3G), we sought to determine whether increasing TGF-β signaling would interfere with CAC tumorigenesis.