Image_6_MICAL2 Facilitates Gastric Cancer Cell Migration via MRTF-A-Mediated CDC42 Activation.jpg
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.
History
References
- https://doi.org//10.1158/1078-0432.ccr-05-1995
- https://doi.org//10.1016/j.brainres.2011.02.016
- https://doi.org//10.1038/onc.2015.14
- https://doi.org//10.3892/mmr.2015.4523
- https://doi.org//10.1242/jcs.202028
- https://doi.org//10.1089/ars.2013.5487
- https://doi.org//10.1242/jcs.089367
- https://doi.org//10.1158/1535-7163.mct-15-0419
- https://doi.org//10.1126/science.1211956
- https://doi.org//10.1038/ncb2871
- https://doi.org//10.1161/circresaha.108.180885
- https://doi.org//10.1097/01.mib.0000437615.98881.31
- https://doi.org//10.1016/j.canlet.2016.03.035
- https://doi.org//10.1074/jbc.m111.276931
- https://doi.org//10.1016/j.cell.2013.12.035
- https://doi.org//10.1038/90054
- https://doi.org//10.18632/oncotarget.6577
- https://doi.org//10.1038/ncb1833
- https://doi.org//10.1016/s0092-8674(03)00278-2
- https://doi.org//10.7314/apjcp.2014.15.12.4745
- https://doi.org//10.1371/journal.pone.0083188
- https://doi.org//10.1074/jbc.ra118.003276
- https://doi.org//10.1083/jcb.201205169
- https://doi.org//10.1016/j.biocel.2010.08.014
- https://doi.org//10.1016/j.gene.2015.02.076
- https://doi.org//10.3892/or.2015.4329
- https://doi.org//10.1523/jneurosci.0333-09.2009
- https://doi.org//10.2741/1667
- https://doi.org//10.1101/gr.4108706
- https://doi.org//10.1074/jbc.m111842200
- https://doi.org//10.1016/j.devcel.2014.10.005
- https://doi.org//10.1111/apha.12920
- https://doi.org//10.1001/jama.1987.03390180052010
- https://doi.org//10.1080/23723556.2017.1384881
- https://doi.org//10.1016/j.canlet.2020.04.019