Expression of heregulin α, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells

Abstract

Background & Aims: Heregulins (HRGs) regulate the proliferation and differentiation of various cell types. However, very little is known about their function in the gastrointestinal tract. The aim of this study was to investigate the role of HRGs on gastrointestinal cells. Methods: We examined the expression of erbB receptors and HRG-α in human gastric cancer cell lines, rat gastrointestinal epithelial cells, and human gastric fibroblasts by Western blot analysis or reverse-transcription polymerase chain reaction. Receptor phosphorylation and heterodimerization induced by HRG-α were detected by Western blot analysis. We also evaluated the in vitro effects of HRG-α on cell proliferation and restitution. Results: Cancer cell lines and rat epithelial cells expressed erbB2 and erbB3, but protein expression of erbB4 was not detected. HRG-α was detected only in gastric fibroblasts. HRG-α activated tyrosine phosphorylation of epidermal growth factor receptor (EGFR), erbB2, and erbB3 and induced not only erbB3/erbB2 but also erbB3/EGFR and erbB2/EGFR heterodimer formation in MKN-28 cancer cells. Simultaneous cultivation of MKN-28 cells with gastric fibroblasts resulted in tyrosine phosphorylation of erbB3 in MKN-28 cells. HRG-α also stimulated proliferation of MKN-28 cells and gastric epithelial cells. Conclusions: The data suggest that HRG-α may affect epithelial cell proliferation through mesenchymal-epithelial interaction in the gastric mucosa. GASTROENTEROLOGY 1999;117:1119-1127