Formation of E-cadherin-mediated cell-cell adhesion activates Akt and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells
Formation of E-cadherin-mediated cell-cell adhesion activates Akt and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells
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DOI：
10.1210/me.2004-0342
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发表时间：
2005-10-01
影响因子：
--
通讯作者：
Liu, K
中科院分区：
文献类型：
--
作者：
Reddy, P;Liu, LA;Liu, K
E-钙粘附素是一种特性良好的黏附分子，在上皮细胞黏附中发挥重要作用。研究发现，E-钙粘附素在人类上皮性癌中经常缺失，它被认为是大多数人类上皮性癌发生过程中的一种肿瘤抑制因子。然而，在卵巢癌的发展过程中，我们的研究数据显示，无论分化程度如何，86.5%的良性、交界性和恶性卵巢癌组织中E-钙粘附素的表达均升高，而正常卵巢组织中不表达E-钙粘附素。因此，我们推测E-钙粘附素在卵巢上皮癌的发生发展中可能起着独特的作用。利用E-钙粘附素表达的卵巢癌细胞株OVCAR-3，我们首次证明了E-钙粘附素介导的细胞-细胞黏附的建立导致Akt和MAPK的激活。AKT的激活是通过磷脂酰肌醇3激酶的激活来实现的，而Akt和MAPK的激活都是通过E-钙粘附素诱导的非配体依赖性的表皮生长因子受体激活来实现的。我们还证明，抑制E-钙粘附素功能会导致细胞增殖迟缓和存活率降低。因此，我们认为E-钙粘附素黏附和下游增殖信号的激活同时形成可能促进卵巢癌细胞的增殖和存活。我们的数据部分解释了为什么E-钙粘附素总是在卵巢肿瘤的发生和发展过程中表达。
E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.