Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.

中文翻译：

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细胞骨架蛋白ADD3的丢失促进多形性胶质母细胞瘤中的肿瘤生长和血管生成。

Adducin 3（ADD3）是肌动蛋白细胞骨架中至关重要的组装因子，已发现在多种癌症中异常表达，包括多形性胶质母细胞瘤（GBM）。先前已经在基于阵列的研究中对其进行了研究，关于其在神经胶质瘤中的功能作用，尚存在争议。在452个神经胶质瘤标本的微阵列分析中，我们发现与正常脑组织相比，GBM中的ADD3显着下调，但在恶性神经胶质瘤中却未见明显下调，这表明其下调可能是恶性进展期间关键事件的基础。我们还发现，ADD3在功能上依赖于细胞-基质相互作用。在我们的体内研究中，可能通过PCNA促进了ADD3缺失的GBM细胞的增殖和血管生成能力，同时抑制了p53和p21的表达，在血管内皮细胞中，VEGF-VEGFR-2介导的活化诱导了促血管生成信号的产生。借助相关的体外，体内和临床数据，我们提供了令人信服的证据证明ADD3在调节GBM生长和血管生成中具有抑癌作用。作为临床前研究，我们的研究可为神经胶质瘤恶性进展的发病机理提供更好的理解，以利于将来的研究。