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.