The role of COX-2-induced heregulin expression and erbB2 phosphorylation in gastrointestinal tract

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Conditioned media (CM) from gastric fibroblasts incubated with prostaglandin E2 (PGE2) or interleukin (IL)-1b, a well known COX-2 inducer, were analyzed for their effect on erbB3 tyrosine phosphorylation in MKN28 gastric epithelial cells. CM from fibroblasts incubated with PGE2 or IL-1b stimulated erbB3 phosphorylation in MKN28 cells. Pre-incubation with celecoxib suppressed erbB3 phosphorylation induced by CM from IL-1b-stimulated gastric fibroblasts. This inhibition was reversed by exogenous PGE2. As with erbB3 phophorylation, IL-1b stimulated both HRG-α and HRG-β mRNA expression, as well as HRG release into gastric fibroblast CM. IL-1b-stimulated HRG expression and release were also inhibited by celecoxib, and exogenous PGE2 restored this inhibitory effect ; suggesting the activation of an IL-1b-COX-2-PGE2 pathway that culminates in the release of HRG from fibroblasts. Next, we examined erbBs expression and relationship between HRG and vascular endothelial growth factor (VEGF) expression in colon cancer. Exogenously added HRG phosphorylated not only erbB2 and erbB3 but also EGFR in all 4 colon cancer cell lines and stimulated VEGF secretion in all 6 colon cancer cell lines. HRG also activated p85-PI3K, Akt, ERK1/2, and p38MAPK and stimulated VEGF mRNA expression and protein secretion in Caco2 colon cancer cells. VEGF secretion was inhibited by each of both specific inhibitors for p38MAPK and nuclear factor kappa B. HRG mRNA expression was well correlated with VEGF mRNA expression in 16 colon cancer biopsy samples. HRG immunoreactivity was observed both in cancer cells and in mesenchymal cells in colon cancer tissues. These data suggest that HRG might affect colon cancer growth by regulating VEGF secretion via erbB3-nuclear factor kappa B pathway through autocrine and paracrine mechanisms.