MICAL2 is a novel nucleocytoplasmic shuttling protein promoting cancer invasion and growth of lung adenocarcinoma

MICAL2 is a tumor-promoting factor involved in cell migration, invasion, deformation, and proliferation not yet fully explored in lung adenocarcinoma (LUAD). This study demonstrated that MICAL2 was overexpressed and cytoplasm-enriched in LUAD tissues. Moreover, high cytoplasmic MICAL2 and/or total MICAL2 expression levels were positively correlated with lymphatic metastasis and shorter overall survival in LUAD patients. MICAL2 promoted LUAD cell proliferation, migration, invasion, and epithelial to mesenchymal transition—all of which involved the AKT and myosin-9 pathways. Furthermore, MICAL2 was identified as a nucleoplasm shuttling protein dependent on myosin-9 and its C-terminal fragment. MICAL2–ΔC—enriched in the nucleus—had less impact on tumor malignancy in LUAD cells in vitro and in vivo. Tumor promotion by MICAL2 was reduced by nuclear-export inhibitor, myosin-9 inhibitor, or si-myosin-9—all of which effectively inhibited MICAL2's nuclear export. Finally, the expression and subcellular location as well as clinical significance of MICAL2 and myosin-9 were analyzed across TCGA data and LUAD tissue arrays. Our data revealed that MICAL2 overexpression and nuclear export were associated with cancer progression; inhibiting its expression and/or nuclear export may provide a new target for LUAD therapy. •MICAL2 promotes cancer invasion and growth of lung adenocarcinoma.•MICAL2 was overexpressed and cytoplasm-enriched in LUAD tissues.•MICAL2 promotes LUAD cell proliferation, migration, invasion, and EMT.•MICAL2 was proved to be a nucleocytoplasmic shuttling protein regulated by myosin-9.•MICAL2 overexpression and nuclear export were associated with cancer progression.