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

EGF受体在胃肠道上皮细胞生长、分化和抗凋亡中的作用。

• 批准号: 09670546
• 负责人: MIYAZAKI Yoshiji
• 金额: $ 1.98万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670546/
• 关键词: EGF receptor; EGF-related peptides; HB-EGF; amphiregulin; apoptosis; STAT3; ras; dominant-negative; 胃粘膜; 修復; 癌化; トランスジェニックマウス

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.

胃肠道癌细胞常过表达EGF受体（EGFR）和/或EGF相关肽，包括肝素结合EGF样生长因子（HB-EGF）和双调节蛋白（AR）。我们研究了活性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。RGM1细胞和IEC-6细胞分别为未转化的大鼠胃上皮细胞系和肠上皮细胞系。我们证明了这些细胞系表达HB-EGF和AR，其转录本是通过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度表达，导致EGFR强烈的酪氨酸组成磷酸化。在致癌ras刺激的细胞中观察到的凋亡抵抗依赖于活跃的egf相关肽自分泌环。我们进一步研究转录因子STAT3是否参与下游抗凋亡信号。我们证明了STAT3在ras刺激的细胞中是组成性激活的，这取决于EGFR的激活。我们还发现，通过引入一个显性阴性突变体破坏STAT3通路，可以消除ras刺激细胞的凋亡抗性。因此，STAT3似乎是过度表达EGFR和/或egf相关肽的癌性胃肠道上皮细胞中抗凋亡信号的重要介质。

项目成果

Shinji Kitamura, Yoshiji Miyazaki, Yasuhisa Shinomura, Shinya Kondo, Shuji Kanayama, and Yuji Matsuzawa.: "Peroxisome proliferator-activated receptor g induces growth arrest and differentiation markers of human colon cancer cells." Jpn.J.Cancer.Res.90(1).

Shinji Kitamura、Yoshiji Miyazaki、Yasuhisa Shinomura、Shinya Kondo、Shuji Kanayama 和 Yuji Matsuzawa.：“过氧化物酶体增殖物激活受体 g 诱导人类结肠癌细胞的生长停滞和分化标记物。”

Yuichi Yasunaga et al.: "Mucosal interleukin-1β and acid secretion in enlarged fold gastritis." Alim.Pharmacol.Ther.11(4). 801-809 (1998)

Yuichi Yasunaga 等人：“扩大皱襞性胃炎中的粘膜白细胞介素 1β 和酸分泌。”Alim.Pharmacol.Ther.11(4) (1998)。

Y.Yasunaga, et al.: "Mucosal interleukin-1β production and acid secretion in enlarged fold gastritis" Aliment.Pharmacol.Ther.11(4). 801-809 (1997)

Y.Yasunaga 等人：“扩大皱襞性胃炎中粘膜白细胞介素 1β 的产生和酸分泌”Aliment.Pharmacol.Ther.11(4) (1997)。

Yoshiji Miyazaki et al.: "Gastrin induces heparin-binding EGF-like growth factor in rat gastric epithelial cells transfected with gastrin receptor." Gastroenterology. 116(1). 78-89 (1999)

Yoshiji Miyazaki 等人：“胃泌素在转染胃泌素受体的大鼠胃上皮细胞中诱导肝素结合 EGF 样生长因子。”

Shusaku Tsutsui et al.: "Induction of heparin-binding epidermal growth factor-like growth factor and amphiregulin mRNAs by gastrin in the rat stomach." Biochem.Biophys.Res.Commun.235(3). 520-523 (1997)

Shusaku Tsutsui 等人：“胃泌素在大鼠胃中诱导肝素结合表皮生长因子样生长因子和双调蛋白 mRNA。”