The gastric
hormone gastrin regulates the organization of the gastric epithelium, but the cellular control mechanisms are yet unknown. Epithelial remodelling typically involves extracellular proteolysis mediated by the
matrix metalloproteinases (
MMPs). Since a gene-array analysis of the
gastric cancer cell line AGS-G(R) suggested that
gastrin increased MMP-9 expression, we examined the control of MMP-9 expression by
gastrin.
Gelatin zymography confirmed
gastrin induction of MMP-9 in AGS-G(R) cells, but showed a small inhibition of MMP-2. Immunocytochemical studies showed that MMP-9 was localized to vesicles that appeared to traffic along the processes that were extended in response to
gastrin.
Gastrin stimulated the invasion of AGS-G(R) cells through artificial basement membrane, which was reduced by an inhibitor of
MMP-2/-9. There was also an increase in MMP-9 in the stomach of patients with elevated plasma
gastrin and
multiple-endocrine neoplasia type 1 (MEN-1) syndrome, suggesting in vivo regulation of MMP-9 expression by
gastrin. Finally, we showed that the expression of 1.9 kb of human MMP-9 gene promoter coupled with
luciferase (MMP-9-luc) was increased 7.65+/-1.2-fold by
gastrin, via a pathway which includes stimulation of
protein kinase C, and activation of Raf and the
mitogen-activated
protein (MAP)
kinase pathway. The tumour suppressor menin (which is mutated in MEN-1 syndrome) inhibited the expression of MMP-9-luc by
gastrin. These results suggest that
gastrin increases MMP-9 expression, which is associated with increased invasion, and this is a putative mechanism regulating remodelling of the gastric epithelium.