Mutations of Regl alpha Are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia

Background & Aims: The Regl alpha gene (Reg) encodes a secretory protein pr oposed to regulate islet beta-cell and gastric mucous cell growth. Reg is e xpressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the id entity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients. Me thods: Reg messenger RNA (mRNA) abundance was quantified by Northern blot i n extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determine d by immunocytochemistry. Mutations of Reg were determined by reverse-trans cription polymerase chain reaction, cloning, and sequencing, and the mutate d protein was expressed in HIT-T15 cells. Results: Reg mRNA abundance was i ncreased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumo rs but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin s timulated Reg mRNA abundance; this was eliminated by the gastrin/cholecysto kinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mut ations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tu mors; in 2 cases, mutation of the initiator methionine residue led to exclu sion of the protein from the secretory pathway. Conclusions: Gastrin regula tes Reg mRNA abundance in human corpus. Mutations of Reg that prevent secre tion are associated with ECL cell carcinoids, suggesting a function as an a utocrine or paracrine tumor suppressor.