Targeting filamin B induces tumor growth and metastasis via enhanced activity of matrix metalloproteinase-9 and secretion of VEGF-A

• Published in: Oncogenesis (New York, NY) NY), 2014-09, Vol.3 (9), p.e119-e119
• Main Authors: Bandaru, S, Zhou, A-X, Rouhi, P, Zhang, Y, Bergo, M O, Cao, Y, Akyürek, L M
• Format: Article
• Language: English
• Subjects: 631/67/1517/1709; 631/67/322; 631/80/86; 692/420/755; Apoptosis; Cell Biology; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original; original-article
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/oncsis.2014.33

Filamins regulate cell locomotion and associate with diverse signaling molecules. We have recently found that targeting filamin A (FLNA) reduces RAS-induced lung adenocarcinomas. In this study, we explored the role of another major filamin isoform, filamin B (FLNB), in tumor development. In contrast to FLNA, we report that targeting FLNB enhances RAS-induced tumor growth and metastasis which is associated with higher matrix metallopeptidase-9 (MMP-9) and extracellular signal-regulated kinase (ERK) activity. Flnb deficiency in mouse embryonic fibroblasts results in increased proteolytic activity of MMP-9 and cell invasion mediated by the RAS/ERK pathway. Similarly, silencing FLNB in multiple human cancer cells increases the proteolytic activity of MMP-9 and tumor cell invasion. Furthermore, we observed that Flnb -deficient RAS-induced tumors display more capillary structures that is correlated with increased vascular endothelial growth factor-A (VEGF-A) secretion. Inhibition of ERK activation blocks phorbol myristate acetate-induced MMP-9 activity and VEGF-A secretion in vitro . In addition, silencing FLNB in human ovarian cancer cells increases secretion of VEGF-A that induces endothelial cells to form more vascular structures in vitro . We conclude that FLNB suppresses tumor growth and metastasis by regulating the activity of MMP-9 and secretion of VEGF-A which is mediated by the RAS/ERK pathway.