DOWN-REGULATION OF THE DOWN-REGULATED IN ADENOMA (DRA) GENE CORRELATES WITH COLON-TUMOR PROGRESSION

The down-regulated in adenoma (DRA) gene was originally identified as a gene that was down-regulated in colon tumors. It encodes a protein,v ith anion transporter function that is expressed predominantly in the mucosa of the lower gastrointestinal tract. In this study, expression of DRA and its cellular distribution have been investigated in a serie s of benign adenomatous polyps and malignant colorectal tumors and in corresponding normal colonic mucosa. We show that DRA mRNA and protein are expressed in all normal colonic tissue specimens with the protein restricted primarily to the terminally differentiated columnar epithe lium and some goblet cells. Apical membrane localization was especiall y apparent in the columnar epithelium. The levels of DRA mRNA transcri pts were down-regulated in all colon tumors examined relative to match ed normal mucosa, with most specimens showing undetectable levels of D RA mRNA (77 of 104 tumors). DRA down-regulation was positively associa ted with colonic tumor progression according to Dukes' stage and was p articularly significant in the early transition from normal mucosa to polyp to adenocarcinoma, DRA expression does not appear to be strictly associated with colonic cell differentiation; rather, its absence and down-regulation were associated with the proliferating component of t he crypt epithelium and with neoplastic transformation, respectively.