Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Oncogene. 2012 May 17;31(20):2512-20. doi: 10.1038/onc.2011.435. Epub 2011 Sep 26.
Ovarian cancer, the most deadly gynecologic malignancy, is often diagnosed late and at the advanced stage when the cancer cells have already migrated and invaded into other tissues and organs. Better understanding of the mechanism of metastasis in ovarian cancer cells is essential to the design of effective therapy. In this study, we investigated the function of scaffolding adaptor protein Gab2 in ovarian cancer cells. Gab2 is found to be overexpressed in a subset of ovarian tumors and cancer cell lines. Gab2 expression mainly regulates the migratory behaviors of ovarian cancer cells. Overexpression of Gab2 promotes the migration and invasion, and downregulates E-cadherin expression in ovarian cancer cells with low-Gab2 expression. Conversely, knockdown of Gab2 expression inhibits the migration and invasion, and promotes E-cadherin expression in ovarian cancer cells with high-Gab2 expression. By expressing Gab2 wild-type and Gab2 mutants that are defective in activation of the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway. Knockdown of Zeb1 expression blocks Gab2-induced suppression of E-cadherin expression and increase in cell invasion. LY294002 and GDC-0941, inhibitors of PI3K, or Rapamycin, an inhibitor of PI3K downstream target mTOR, can reverse the effects of Gab2 on migration and invasion. Overall, our studies reveal that Gab2 overexpression, via activation of the PI3K-Zeb1 pathway, promotes characteristics of EMT in ovarian cancer cells.
卵巢癌是最致命的妇科恶性肿瘤，通常在晚期和癌症细胞已经转移和侵袭到其他组织和器官时才被诊断出来。更好地了解卵巢癌细胞转移的机制对于设计有效的治疗方法至关重要。在这项研究中，我们研究了支架衔接蛋白 Gab2 在卵巢癌细胞中的功能。发现 Gab2 在一部分卵巢肿瘤和癌细胞系中过度表达。Gab2 的表达主要调节卵巢癌细胞的迁移行为。Gab2 的过表达促进了迁移和侵袭，并下调了低 Gab2 表达的卵巢癌细胞中 E-钙黏蛋白的表达。相反，下调 Gab2 的表达抑制了迁移和侵袭，并促进了高 Gab2 表达的卵巢癌细胞中 E-钙黏蛋白的表达。通过表达 Gab2 野生型和 Gab2 突变体，这些突变体在激活 PI3K 和 Shp2-Erk 途径方面存在缺陷，我们发现 Gab2 通过激活 PI3K 途径抑制 E-钙黏蛋白的表达，并增强转录因子 Zeb1 的表达，从而促进上皮间质转化（EMT）、细胞迁移和侵袭。下调 Zeb1 的表达可阻断 Gab2 诱导的 E-钙黏蛋白表达下调和细胞侵袭增加。PI3K 的抑制剂 LY294002 和 GDC-0941 或 PI3K 下游靶点 mTOR 的抑制剂 Rapamycin 可逆转 Gab2 对迁移和侵袭的影响。总之，我们的研究表明，Gab2 通过激活 PI3K-Zeb1 通路的过表达促进了卵巢癌细胞 EMT 的特征。
