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Overexpression of TIS21/BTG2/PC3 inhibits invadopodia formation in highly metastatic breast cancer cells

Choi, Jung-A; Lim, In Kyoung
Department of Biochemistry & Molecular Biology
Cancer cell invasion across a basement membrane depends on the proteolytic degradation of extracellular matrix, and that is initiated by formation of actin-driven membrane protrusions, called invadopodia. However, mechanisms underlying invadopodia formation remain largely unknown. In this study, we found that TIS21/BTG2/PC3, tumor suppressor gene, suppress invadopodia formation in highly invasive breast cancer cells, MDA-MB-231. To understand the downstream mechanism by which TIS21 modulates invadopodia formation, we found that ROS (reactive oxygen species) generated by the NADPH oxidase (Nox) system, which are necessary for invadopodia formation and function, was significantly attenuated by overexpression of TIS21. Furthermore, overexpression of TIS21 markedly inhibits mRNA level of Nox1 and Nox4, but not p22phox, in one of NADPH oxidase system. In contrast, mouse embryo fibroblasts lacking TIS21 (MEF-TIS21-/-) formed invadopodia for extracellular matrix degradation and showed the elevated mRNA level of Nox1 and Nox4, suggesting TIS21 contributes to invadopodia formation through the NADPH oxidase system. Noticeably, TIS21 overexpression caused the reorganization of actin-assoicated protein and cytoskelectal protein such as F-actin and vimentin. Similarly, inhibition of NADPH oxidase-derived ROS generation by using DPI induces reorganization of these proteins, suggesting that NADPH oxidase-derived ROS generation play a critical role to distribution of actin-assoicated protein and cytoskelectal protein. Taken together, our results demonstrate, for the first time, that the 'BTG2-ROS’-linked cascades is required for the formation of invadopodia in highly invasive breast cancer cells and may provide insight into mechanisms of metastatic signaling in breast cancer.
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