Abstract
Previous studies on cancer cell invasion were primarily focused on its migration because these two events were often considered biologically equivalent. Here we found that T24T cells exhibited higher invasion but lower migration abilities than T24 cells. Expression of Rho-GDPases was much lower and expression of SOD2 was much higher in T24T cells than those in T24 cells. Indeed, knockdown of SOD2 in T24T cells can reverse the cell migration but without affecting cell invasion. We also found that SOD2 inhibited the JNK/c-Jun cascade, and the inhibition of c-Jun activation by ectopic expression of TAM67 impaired Rho-GDPases expression and cell migration in T24T shSOD2 cells. Further, we found that Sp1 can upregulate SOD2 transcription in T24T cells. Importantly, matrix metalloproteinase-2 (MMP-2) was overexpressed in T24T and participated in increasing its invasion, and MMP-2 overexpression was mediated by increasing nuclear transport of nucleolin, which enhanced mmp-2 mRNA stability. Taken together, our study unravels an inverse relationship between cell migration and invasion in human bladder cancer T24T cells and suggests a novel mechanism underlying the divergent roles of SOD2 and MMP-2 in regulating metastatic behaviors of human bladder T24T in cell migration and invasion.
Highlights
The acquisition of migratory and invasive properties by cancer cells is a key development preceding metastasis [1, 2]
Some recent studies indicate that cell migration is not consistent with the tendency of cell metastasis or invasion
The Wnt/βCatenin signaling pathway is implicated in reducing melanocyte cell migration but promoting melanoma cell metastasis [38]. p120 catenin is required for HER2/ ErbB2-induced breast cancer cell migration through the activation of CDC42 and Rac1 expression, while the overexpression of p120 in MCF-10A cells has no effect on cell invasion [39]. α-catenin is implicated in inducing human colonic cancer cell migration but not cell invasion [40]
Summary
The acquisition of migratory and invasive properties by cancer cells is a key development preceding metastasis [1, 2]. RhoGTPases, including CDC42 and Rac, play essential roles in the process of cell migration, including adhesion, subsequent loss of attachment, re-adhesion, polarization, and cytoskeletal organization [6]. Given the importance of CDC42 and Rac in the cell migratory events, perturbation of the natural balance of these GTPases in a cell may lead to phenotypes of metastasis. Cancer cell metastasis consists of multiple steps: www.impactjournals.com/oncotarget infiltration into the linking tissue, entrance into the blood or immune system, and the formation of a new tumor in a distant organ. Hydration of the extracellular matrix is crucially important for cancer cell invasion and metastasis, a process that tumor cells promote through the secretion of proteins such as matrix metalloproteinase-2 (MMP-2) and MMP-9. MMP-2 has been associated with the metastasis of many cancers, including colorectal cancer [7], ovarian cancer [8], and breast cancer [9], but it does not have a clear association with bladder cancer invasion
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