DECREASED EXPRESSION OF NHE3 IN COLON CANCER EPITHELIUM IS ASSOCIATED WITH DNA DAMAGE, INCREASED LOCAL INFLAMMATION AND TUMOR GROWTH

Dysregulation of intracellular and extracellular pH in cancer is thought to contribute matrix remodeling, metastasis, favors cell migration proliferation. Although the primary attention has been focused on role ubiquitous Na+/H+ exchanger 1 isoform (SLC9A1), NHE3 (SLC9A3), predominant apical colonic surface epithelium pathogenesis colon not investigated. We examined expression matched biopsies from patients with sporadic colorectal cancer, tested effects knockout intestinal carcinogenesis, inflammation, DNA damage, gut microbiota ApcMin/+ mice, evaluated intrinsic knockdown carcinoma SK-CO15 cells. mRNA was significantly reduced human patients. NHE3-/-ApcMin/+ at 15 weeks age (significant mortality observed beyond this time point) had lower body weights, increased mucosal tumor numbers, evidence enhanced damage epithelium, demonstrated significant alteration microbiota. The latter primarily driven by deficiency. In absence inflammatory microbial pressors, ca. 70% cells led pH, elevated dramatic differences their transcriptomic profile, susceptibility proliferation, decreased apoptosis adhesion proteins. Our findings suggest that loss tumors profound consequences for progression behavior.