Article: article from journal or magazin.
Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor.
Journal of Biological Chemistry
Publication types: Journal Article
Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA-mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1(N17)) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization.
Adenocarcinoma/embryology, Adenocarcinoma/pathology, Adenoviridae/genetics, Caveolin 1/metabolism, Cell Line, Tumor, Cell Movement, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms/metabolism, Lung Neoplasms/pathology, Macrophage Migration-Inhibitory Factors/physiology, Membrane Microdomains/metabolism, Models, Biological, Mutation, Neoplasm Invasiveness, RNA, Small Interfering/metabolism, rhoA GTP-Binding Protein/metabolism
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