Targeting filamin B induces tumor growth and metastasis via enhanced activity of matrix metalloproteinase-9 and secretion of VEGF-A
2014 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 3, e119- p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group , 2014. Vol. 3, e119- p.
IdentifiersURN: urn:nbn:se:liu:diva-114452DOI: 10.1038/oncsis.2014.33ISI: 000348446100002PubMedID: 25244493OAI: oai:DiVA.org:liu-114452DiVA: diva2:789912
Funding Agencies|Swedish Society of Medicine; Magnus Bergvalls Foundation; Jubileumfonden; Sahlgrenska University Hospital; Royal Society of Arts and Sciences in Goteborg; Assar Gabrielssons Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Swedish Cancer Foundation2015-02-202015-02-202015-03-03