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

COX-2诱导的heregulin表达和erbB2磷酸化在胃肠道中的作用

基本信息

批准号：
16590641
负责人：
SAKAMOTO Choitsu
金额：
$ 2.56万
依托单位：
NIPPON MEDICAL SCHOOL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590641/
关键词：
heregulin erbB2 cyclooxygenase-2 fibroblast gastric ulcer colon cancer cyclooxygenase2 PGE_2 erbB3 胃線維芽細胞

项目摘要

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.

用前列腺素E2（PGE 2）或白细胞介素（IL）-1b（一种众所周知的考克斯-2诱导剂）孵育胃成纤维细胞的条件培养基（CM），分析它们对MKN 28胃上皮细胞中erbB 3酪氨酸磷酸化的影响。在MKN 28细胞中，来自与PGE 2或IL-1b孵育的成纤维细胞的CM刺激erbB 3磷酸化。塞来昔布预孵育抑制IL-1b刺激的胃成纤维细胞中CM诱导的erbB 3磷酸化。这种抑制作用可被外源性PGE 2逆转。与erbB 3磷酸化一样，IL-1b刺激HRG-α和HRG-β mRNA表达，以及HRG释放到胃成纤维细胞CM中。IL-1b刺激的HRG表达和释放也被塞来昔布抑制，外源性PGE 2恢复了这种抑制作用;这表明IL-1b-COX-2-PGE 2通路的激活最终导致HRG从成纤维细胞中释放。接下来，我们研究了结肠癌中erbBs的表达以及HRG和血管内皮生长因子（VEGF）表达之间的关系。外源性HRG不仅磷酸化erbB 2和erbB 3，而且在所有4个结肠癌细胞系中磷酸化EGFR，并刺激所有6个结肠癌细胞系中VEGF的分泌。HRG还激活了Caco 2结肠癌细胞中的p85-PI 3 K、Akt、ERK 1/2和p38 MAPK，并刺激VEGF mRNA表达和蛋白分泌。p38 MAPK和核因子κ B的特异性抑制剂均抑制VEGF分泌。16例结肠癌组织中HRG mRNA表达与VEGF mRNA表达呈显著相关。结肠癌组织中的癌细胞和间充质细胞中均观察到HRG免疫反应。提示HRG可能通过自分泌和旁分泌机制，通过erbB 3-核因子κ B途径调节VEGF的分泌，从而影响结肠癌的生长。