Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) supports oncogenic signaling in a number of solid and hematologic tumors. Little is known about the role of NEDD9 in ovarian carcinoma (OC), but available data suggest elevated mRNA and protein expression in advanced stage high-grade cancers. We used a transgenic MISIIR-TAg mouse OC model combined with genetic ablation of Nedd9 to investigate its action in the development and progression of OC. A Nedd9^-/- genotype delayed tumor growth rate, reduced incidence of ascites, and reduced expression and activation of signaling proteins including SRC, STAT3, E-cadherin, and AURKA. Cell lines established from MISIIR-TAg;Nedd9^-/- and MISIIR-TAg;Nedd9^+/+ mice exhibited altered migration and invasion. Growth of these cells in a syngeneic allograft model indicated that systemic Nedd9 loss in the microenvironment had little impact on tumor allograft growth, but in a Nedd9 wild-type background Nedd9^-/- allografts exhibited significantly reduced growth, dissemination, and oncogenic signaling compared to Nedd9^+/+ allografts. Gene expression analysis revealed that Nedd9^+/+ tumors exhibited more mesenchymal "stem-like" transcriptional program, including increased expression of Aldh1a1 and Aldh1a2. Conversely, loss of Nedd9 resulted in increased expression of differentiation genes, including fallopian tube markers Foxj1, Ovgp1, and Pax8. Collectively, these data suggest that tumor cell-intrinsic Nedd9 expression promotes OC development and progression by broad induction of oncogenic protein signaling and stem/mesenchymal gene expression.

中文翻译：

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NEDD9 促进致癌信号、干/间质基因特征以及小鼠侵袭性卵巢癌的生长。


神经前体细胞表达的发育下调 9 (NEDD9) 支持许多实体瘤和血液肿瘤中的致癌信号传导。关于 NEDD9 在卵巢癌 (OC) 中的作用知之甚少，但现有数据表明晚期高级别癌症中 mRNA 和蛋白质表达升高。我们使用转基因 MISIIR-TAg 小鼠 OC 模型结合 Nedd9 的基因消融来研究其在 OC 发生和进展中的作用。 Nedd9 ^-/-基因型可延缓肿瘤生长速度，降低腹水发生率，并减少信号蛋白（包括 SRC、STAT3、E-钙粘蛋白和 AURKA）的表达和激活。从 MISIIR-TAg;Nedd9 ^-/-和 MISIIR-TAg;Nedd9 ^+/+小鼠建立的细胞系表现出改变的迁移和侵袭。这些细胞在同基因同种异体移植模型中的生长表明，微环境中的系统性 Nedd9 缺失对肿瘤同种异体移植物的生长几乎没有影响，但在 Nedd9 野生型背景下，与相比，Nedd9 ^-/-同种异体移植物表现出显着减少的生长、传播和致癌信号传导Nedd9 ^+/+同种异体移植物。基因表达分析显示，Nedd9 ^+/+肿瘤表现出更多的间充质“干样”转录程序，包括 Aldh1a1 和 Aldh1a2 表达增加。相反，Nedd9 的缺失导致分化基因的表达增加，包括输卵管标记 Foxj1、Ovgp1 和 Pax8。总的来说，这些数据表明肿瘤细胞固有的 Nedd9 表达通过广泛诱导致癌蛋白信号传导和干/间质基因表达来促进 OC 的发生和进展。