Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

摘要: 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 their action cancer remain unclear. We previously that expression FBLN3 is suppressed by promoter hypermethylation associated with invasiveness aggressive non-small cell lung cancer. In this study, we evaluated roles signaling mechanism stem cells (CSCs). Forced invasion migration adenocarcinoma decreased epithelial-to-mesenchymal transition (EMT) activators, including N-cadherin Snail. Stemness activities were also indicated decrease spheroid formation levels stemness markers such Sox2 β-catenin. These effects mediated glycogen synthase kinase-3β, GSK3β/β-catenin pathway, upstream regulators GSK3β, phosphoinositide 3-kinase (PI3K)/AKT insulin-like growth factor-1 receptor (IGF1R), inactivated FBLN3. Moreover, IGF1R was be direct target FBLN3, which competitively inhibited factor (IGF) action. To confirm effect on CSCs, aldehyde dehydrogenase-positive (ALDH+) A549 CSCs sorted treated recombinant protein. clearly EMT, activity over-activated IGF1R/PI3K/AKT/GSK3β pathway ALDH+ CSC subpopulation. addition, injection protein around subcutaneous xenografts established athymic nude mice significantly progression. Overall, our results show suppresses both EMT self-renewal modulating would useful an alternative therapy.