title: Targeting filamin B induces tumor growth and metastasis via enhanced activity of matrix metalloproteinase-9 and secretion of VEGF-A.
abstract: 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.Oncogenesis (2014) 3, e119; doi:10.1038/oncsis.2014.33; published online 22 September 2014.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Bandaru
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
authors.forename: A-X
authors.initials: AX
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Rouhi
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Bergo
authors.affiliation: 1] Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden [2] Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 1] Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden [2] Department of Clinical Pathology and Genetics, The Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: L M
authors.initials: LM
authors.lastname: Akyürek