Role of EGF receptor in the growth, differentiation and apoptosis resistance of gastrointestinal epithelial cells.

胃肠道癌细胞常过表达表皮生长因子受体（EGFR）和/或EGF相关肽，包括肝素结合EGF样生长因子（HB-EGF）和双调蛋白（AR），我们研究了活跃的EGF相关肽自分泌环在胃肠道上皮细胞生长和抗凋亡中的作用。我们证明这些细胞系表达HB-EGF和AR，其中转录本是通过EGFR和G蛋白偶联受体介导的生长信号诱导的。致癌ras诱导这些生长因子的过表达，导致EGFR的强烈和组成性酪氨酸磷酸化。在致癌ras中观察到的凋亡抵抗，刺激的细胞依赖于活性EGF相关肽自分泌环。我们进一步研究了转录因子STAT 3是否参与了下游抗凋亡信号。我们证明STAT 3在ras刺激的细胞中依赖于EGFR的激活而组成性激活，我们还发现通过引入显性负突变体来破坏STAT 3通路可以消除ras刺激的细胞的凋亡抗性，因此，STAT 3似乎是过表达EGFR和/或EGF相关肽的癌性胃肠上皮细胞中抗凋亡信号的重要介质。

Gastrointestinal carcinoma cells often overexpress EGF receptor (EGFR) and/or EGF-related peptides including heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR).We investigated the role of the active EGF-related peptide autocrine loop in the growth and apoptosis resistance of gastrointestinal epithelial cells.RGM1 cells and IEC-6 cells are nontransformed rat gastric and intestinal epithelial cell lines, respectively.We demonstrated that these cell lines express HB-EGF and AR, of which transcripts are induced through EGFR- and G-protein-coupled receptor-mediated growth signals.Oncogenic ras induced overexpression of these growth factors resulting in the strong and constitutive tyrosine phosphorylation of EGFR.The apoptosis resistance observed in the oncogenic ras-stimulated cells was dependent on the active EGF-related peptide autocrine loop. We further investigated if the transcription factor STAT3 was involved in the downstream anti-apoptotic signals. We demonstrated that STAT3 is constitutively activated in the ras-stimulated cells depending on the activation of EGFR.We also found that disruption of the STAT3 pathway by introduction of a dominant-negative mutant abolishes the apoptosis resistance of the ras-stimulated cells.Thus, STAT3 appears to be an important mediator of the anti-apoptotic signal in cancerous gastrointestinal epithelial cells which overexpress EGFR and/or EGF-related peptides.