Expression of heregulin alpha, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells.
OBJECTIVE
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-alpha 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-alpha were detected by Western blot analysis. We also evaluated the in vitro effects of HRG-alpha 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-alpha was detected only in gastric fibroblasts. HRG-alpha 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-alpha also stimulated proliferation of MKN-28 cells and gastric epithelial cells.


CONCLUSIONS
The data suggest that HRG-alpha may affect epithelial cell proliferation through mesenchymal-epithelial interaction in the gastric mucosa.
Noguchi
H
H
Second Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
Sakamoto
C
C
Wada
K
K
Akamatsu
T
T
Uchida
T
T
Tatsuguchi
A
A
Matsui
H
H
Fukui
H
H
Fujimori
T
T
Kasuga
M
M
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000502:physiology; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004064:Digestive System / Q000166:cytology / Q000378:metabolism; D019281:Dimerization; D005347:Fibroblasts / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013270:Stomach / Q000166:cytology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D004247:DNA; D008024:Ligands; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; D014443:Tyrosine; C117463:heregulin alpha