Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors
Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors
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DOI：
10.1158/0008-5472.can-04-0978
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Seva, C
中科院分区：
文献类型：
--
作者：
Ferrand, A;Bertrand, C;Seva, C
MTI/G-Gly小鼠和HGAS小鼠分别过表达甘氨酸延伸胃泌素(G-Gly)和孕激素，表现为结肠粘膜过度增殖和过度增殖，并增加了对肠道肿瘤的易感性。在这里，我们使用这些转基因小鼠在体内分析细胞内信号通路的调节，这可能是胃泌素前体增殖效应的原因。应用免疫荧光和免疫印迹技术研究MTI/G-Gly、HGAS和野生型FVB/N小鼠结肠组织中信号分子和细胞间黏附分子的表达、激活和定位。这些分析表明，与野生型对照动物相比，mTI/G-Gly和hGAS小鼠Src酪氨酸激酶及其相关信号通路[磷脂酰肌醇S激酶(PI3K)/Akt，Janus激活激酶(JAK)2，信号转导和转录激活因子(STAT)3，以及细胞外信号调节激酶(ERK)]上调，并过度表达转化生长因子-α。相反，胃泌素前体的过度表达既不影响STAT1的激活状态，也不影响黏附蛋白(粘着斑激酶、钙粘附素和连接素)的表达和分布。我们首次报道，在MTI/G-Gly和HGAS小鼠中，从正常的结肠上皮到过度增殖的上皮的转变可能是由于Src、PI3K/Akt、JAK2、STAT3、ERKs和转化生长因子-α上调的结果。在这些转基因模型中，细胞黏附的解除调控是肿瘤进展的晚期事件，不会发生。
MTI/G-Gly mice and hGAS mice, overexpressing glycine-extended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol S-kinase (PI3K)/ Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-alpha (TGF-alpha). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins (focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyper-proliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-alpha. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models.