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

S Bandaru; A-X Zhou; P Rouhi; Y Zhang; M O Bergo; Y Cao; L M Akyürek

doi:10.1038/oncsis.2014.33

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

Oncogenesis. 2014 Sep 22;3(9):e119. doi: 10.1038/oncsis.2014.33.

Authors

S Bandaru¹, A-X Zhou¹, P Rouhi², Y Zhang², M O Bergo³, Y Cao⁴, L M Akyürek⁵

Affiliations

¹ Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
² Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
³ The Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden.
⁴ 1] Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden [2] Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
⁵ 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.

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.