Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia.
OBJECTIVE
The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients.


METHODS
Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells.


RESULTS
Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin 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. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway.


CONCLUSIONS
Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.
Higham
A D
AD
The Physiological Laboratory, University of Liverpool, Liverpool, England.
Bishop
L A
LA
Dimaline
R
R
Blackmore
C G
CG
Dobbins
A C
AC
Varro
A
A
Thompson
D G
DG
Dockray
G J
GJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002276:Carcinoid Tumor / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004701:Endocrine Gland Neoplasms / Q000097:blood; D004759:Enterochromaffin Cells / Q000473:pathology*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood* / Q000502:physiology; D006801:Humans; D051847:Lithostathine; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000097:blood; D013274:Stomach Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014018:Tissue Distribution / Q000502:physiology
D002135:Calcium-Binding Proteins; D005755:Gastrins; D051847:Lithostathine; D009419:Nerve Tissue Proteins; C497617:REG1A protein, human; D012333:RNA, Messenger; D008715:Methionine