Journal
ONCOGENE
Volume 33, Issue 30, Pages 3908-3917Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.373
Keywords
FBLN3; lung; EMT; cancer stem cells; IGF1R/PI3K/AKT/GSK3 beta pathway
Funding
- Ministry of Science, ICT & Future Planning (Nuclear Research and Development Program) of the Republic of Korea
- Korea Atomic Energy Research Institute
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Fibulins (FBLNs), a family of extracellular matrix proteins, have recently been shown to act as tumor suppressors or activators in different cancers, and the underlying molecular mechanisms of their action in cancer remain unclear. We have previously shown that the expression of FBLN3 is suppressed by promoter hypermethylation and is associated with invasiveness in aggressive non-small cell lung cancer. In this study, we evaluated the roles and signaling mechanism of FBLN3 in lung cancer stem cells (CSCs). Forced expression of FBLN3 suppressed invasion and migration of lung adenocarcinoma cells and decreased the expression of epithelial-to-mesenchymal transition (EMT) activators, including N-cadherin and Snail. Stemness activities of lung adenocarcinoma cells were also suppressed by FBLN3 as indicated by a decrease in spheroid formation and the levels of stemness markers such as Sox2 and beta-catenin. These effects of FBLN3 were mediated by the glycogen synthase kinase-3 beta, GSK3 beta/beta-catenin pathway, and the upstream regulators of GSK3 beta, including phosphoinositide 3-kinase (PI3K)/AKT and insulin-like growth factor-1 receptor (IGF1R), were inactivated by FBLN3. Moreover, IGF1R was shown to be a direct target of FBLN3, which competitively inhibited insulin-like growth factor (IGF) action. To confirm the effect of FBLN3 on lung CSCs, aldehyde dehydrogenase-positive (ALDH +) A549 lung CSCs were sorted and treated with recombinant FBLN3 protein. FBLN3 clearly suppressed EMT, stemness activity and the over-activated IGF1R/PI3K/AKT/GSK3 beta pathway of the ALDH + CSC subpopulation. In addition, injection of recombinant FBLN3 protein around subcutaneous xenografts established with ALDH + CSCs in athymic nude mice significantly suppressed tumor growth and progression. Overall, our results show that FBLN3 suppresses both EMT and self-renewal of the lung CSCs by modulating the IGF1R/PI3K/AKT/GSK3 beta pathway and that FBLN3 would be useful as an alternative CSC therapy.
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