Cholecystokinin-2 receptor modulates cell adhesion through β1-integrin in human pancreatic cancer cells
Cholecystokinin-2 receptor modulates cell adhesion through β1-integrin in human pancreatic cancer cells
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DOI：
10.1038/sj.onc.1209484
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发表时间：
2006-07-01
期刊：
影响因子：
8
通讯作者：
Seva, C.
中科院分区：
文献类型：
--
作者：
Cayrol, C.;Clerc, P.;Seva, C.
一些证据表明，胃泌素和CCK-2受体（CCK-2 R）可能有助于胰腺癌的发生，通过调节过程，如增殖，细胞粘附或迁移。在目前的研究中，我们使用了“癌症基因阵列”，并确定β 1-整合素亚基作为一个新的胃泌素调节基因在人类胰腺癌细胞。我们还证明了Src家族激酶和磷脂酰肌醇-3-激酶（PI-3-激酶）通路在胃泌素诱导的β 1-整合素表达中起着至关重要的作用。我们的研究结果还表明，胃泌素通过β 1-整联蛋白调节细胞基质粘附。事实上，使用阻断性抗β 1-整联蛋白单克隆抗体，我们完全逆转了胃泌素诱导的细胞基质粘附的增加。此外，我们观察到，响应于胃泌素，β 1-整联蛋白被Src家族激酶酪氨酸磷酸化，并与桩蛋白（一种参与粘着斑和整联蛋白信号传导的支架蛋白）相关。这一机制可能与胃泌素诱导的细胞粘附有关。此外，我们在体内表明，在Elas-CCK 2小鼠的胰腺中靶向CCK 2 R表达导致β 1-整联蛋白的过表达。这一过程可能有助于在这些转基因动物中观察到的胰腺肿瘤的发展。
Several lines of evidence suggest that gastrin and the CCK-2 receptor (CCK2R) could contribute to pancreatic carcinogenesis by modulating processes such as proliferation, cell adhesion or migration. In the current study, we used a 'cancer gene array' and identified beta 1-integrin subunit as a new gastrin-regulated gene in human pancreatic cancer cells. We also demonstrated that Src family kinases and the phosphatidylinositol-3-kinase (PI-3-kinase) pathway play a crucial role in the expression of beta 1-integrin induced by gastrin. Our results also showed that gastrin modulates cell-substrate adhesion via beta 1-integrin. Indeed, using blocking anti-beta 1-integrin monoclonal antibodies, we completely reversed the increase in cell substrate adhesion induced by gastrin. In addition, we observed that in response to gastrin, beta 1-integrin is tyrosine phosphorylated by Src family kinases and associates with paxillin, a scaffold protein involved in focal adhesion and integrin signalling. This mechanism might be involved in gastrin-induced cell adhesion. Moreover, we showed in vivo that targeted CCK2R expression in the pancreas of Elas-CCK2 mice leads to the overexpression of beta 1-integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.