ADD3 loss in glioblastoma is associated with increased angiogenesis and malignancy

Abstract

<p>Introduction: Adducin 3 (ADD3) is one of the major functional component in the cytoskeleton. Dysregulation of ADD3 has been implicated in various diseases including cancer and participate in different signaling transductions. However, little is known about the functional properties of ADD3 in cancer, its role in cancer biology remains unclear and controversial. We aim to delineate the role of ADD3 dysregulation in GBM pathogenesis and to unravel the underlying molecular mechanisms.</p><p>Methods: Microarray datasets were used to analyze the gene expression of ADD3 in normal tissue and grade II, III, IV gliomas. Gene expression levels were verified by western blot, qPCR and immuno-histological analyses by using human clinical specimens. Luciferase-expressing ADD3 stable knockdown U87 malignant glioma cells were injected to immunocompromised mice subcutaneously and orthotopically for xenograft models. ADD3 stable knockdown U87 cells were co-cultured with human endothelial cells (HUVEC) to assess the functional changes.</p><p>Findings: Our study demonstrated significant downregulation of ADD3 in human GBM when compared with lower-grade gliomas. Downregulation of ADD3 was only shown in GBM (i.e., WHO grade IV lesion) but not in grade II and grade III tumor. Importantly, we found that ADD3 downregulation is associated with poor clinical outcome in GBM patients. And that ADD3 knock-down enhanced tumor growth <em>in vivo</em>, possibly mediated by promoting angiogenesis.</p><p>Conclusions: These findings suggest that ADD3 is associated with glioma malignancy, implying that cancer progression may occur along with the loss of ADD3. It may contribute towards tumor growth by enhancing angiogenesis.</p>