SRC ACTIVATION IN MALIGNANT AND PREMALIGNANT EPITHELIA OF BARRETTS-ESOPHAGUS

Background & Aims: The neoplastic progression of Barrett's esophagus ( BE) may involve genomic instability, inactivation of tumor suppressor genes, or activation of oncogenes. Because activation of Src tyrosine kinase occurs in malignant and premalignant epithelia of the colon, th e aim of this study was to determine whether BE is associated with cha nges in Src expression and activity. Methods: Src expression and in vi tro protein-tyrosine kinase activity in endoscopic tissue samples of B E and esophageal adenocarcinoma were measured and compared with expres sion and activity in normal esophagus and duodenum from the same patie nt. Src phosphorylation was assessed by immunoblotting using antiphosp hotyrosine antibodies and two-dimensional tryptic phosphopeptide mappi ng. Results: Src-specific activity was 3-4-fold higher in BE and 6-fol d higher in esophageal adenocarcinoma than in control tissues. Differe nt regions of BE from the same patient showed heterogeneity in Src act ivity compared with the uniform Src activity observed in different reg ions of normal esophagus and duodenum. In all tissues, Src kinase acti vity and protein were associated preferentially with the Triton X-100- soluble rather than -insoluble fraction. Immunoblotting and two-dimens ional tryptic phosphopeptide mapping showed dephosphorylation of Src a t Tyr527 in BE. Conclusions: Src is activated in BE, in part, because of dephosphorylation of Tyr527. Src activation and its heterogeneous e xpression occur before development of dysplasia or carcinoma in BE.