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 to extracellular matrix remodeling, cancer metastasis, and favors cell migration and proliferation. Although the primary attention has been focused on the role of the ubiquitous Na⁺/H⁺ exchanger 1 isoform (SLC9A1), the role of NHE3 (SLC9A3), the predominant apical isoform in colonic surface epithelium in the pathogenesis of colon cancer has not been investigated.

We examined the NHE3 expression in matched colonic biopsies from patients with sporadic colorectal cancer, tested the effects of NHE3 knockout on intestinal carcinogenesis, inflammation, DNA damage, and gut microbiota in Apc^Min/+ mice, and evaluated the intrinsic effects of NHE3 knockdown in colonic carcinoma SK-CO15 cells.

NHE3 mRNA expression was significantly reduced in colorectal cancer in human patients. NHE3^-/-Apc^Min/+ evaluated at 15 weeks of age (significant mortality was observed beyond this time point) had lower body weights, increased mucosal inflammation, increased colonic tumor numbers, evidence of enhanced DNA damage in the tumor surface epithelium, and demonstrated significant alteration in the gut microbiota. The latter was primarily driven by NHE3 deficiency. In the absence of the inflammatory and microbial pressors, ca. 70% knockdown of NHE3 expression in SK-CO15 cells led to reduced intracellular pH, elevated apical pH, dramatic differences in their transcriptomic profile, increased susceptibility to DNA damage, increased proliferation, decreased apoptosis and reduced adhesion to extracellular matrix proteins.

Our findings suggest that loss of NHE3 in the surface epithelium of colonic tumors has profound consequences for cancer progression and behavior.