Abstract
Aims and Hypothesis: Cell migration is driven by the reorganization of the actin cytoskeleton. Although MICAL2 is known to mediate the oxidation of actin filaments to regulate F-actin dynamics, relatively few studies have investigated the potential role of MICAL2 during cancer cell migration.Methods: The migratory ability of gastric cancer cells was measured by wound healing and transwell assays. The relationship between MICAL2 expression and MRTF-A nuclear localization was analyzed using gene overexpression and knockdown strategies. The production of reactive oxygen species (ROS) was evaluated by DCFH-DA staining. mRNA and protein levels of MMP9 were measured using qPCR and immunoblotting analysis. The activities of CDC42 and RhoA were assessed using pulldown assays.Results: Depletion of MICAL2 markedly reduced gastric cancer cell migration. Mechanistically, silencing of MICAL2 inhibited the nuclear translocation of MRTF-A in response to EGF and serum stimulation, whereas the contents of MRTF-A remained unchanged. Further analysis showed that silencing of MICAL2 decreased the activation of CDC42 as well as mRNA and protein levels of MMP9. Ectopic expression of MICAL2 augmented MRTF-A levels in the nucleus, and promoted the activation of CDC42, MMP9 expression, and gastric cancer cell migration. Moreover, silencing of MRTF-A inhibited the CDC42 activation induced by overexpression of MICAL2. In addition, MICAL2-induced ROS generation contributed to the effect exerted by MICAL2 on MRTF-A nuclear translocation.Conclusion: Together, these results provide evidence that MICAL2 facilitates gastric cancer cell migration via positive regulation of nuclear translocation of MRTF-A and subsequent CDC42 activation and MMP9 expression.
Highlights
The first member of the molecule interacting with CasL family (MICAL) was discovered in 2002 (Suzuki et al, 2002)
Since MICAL2 is required for the upregulation of nuclear Myocardin-related transcription factor A (MRTF-A) levels, we considered that MICAL2 might activates serum response factor (SRF)/MRTF-A signaling by regulating RhoA activity
Increased occupancy of the MMP9 promoter by MRTF-A was observed in EGFtreated BGC-823 cells, consistent with the role of EGF in promoting MMP9 transcription (Figure 6G). These results indicated that MICAL2 may promote gastric cancer cell migration through MRTF-A-dependent cell division control protein 42 homolog (CDC42) activation and MMP9 expression
Summary
The first member of the molecule interacting with CasL family (MICAL) was discovered in 2002 (Suzuki et al, 2002). The main function of the MICAL proteins is associated with cytoskeleton remodeling and fundamental biological processes such as cytokinetic abscission, vesicle trafficking, axon growth, and cell migration (Giridharan and Caplan, 2014; Fremont et al, 2017). Among these members, MICAL2 is constitutively active in eukaryotic cells (Giridharan et al, 2012). Like other normal human cells, cancer cells use actin remodeling for migration and invasion into surrounding tissue or vasculature during tumor progression and metastasis. Despite the known role of MICAL2 in actin oxidation (Yoon and Terman, 2018), how MICAL2 influences cancer cell migration remains largely unknown
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