Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells.

Skp2 is one of the components of the E3 ubiquitin ligase which is required for the degradation of tumor suppressor p27. Overexpression of this oncogene is frequently found in human cancers and has been shown to be associated with poor prognosis. In addition to induce p27 degradation and enhance cellular proliferation, Skp2 also plays a role in promoting tumor metastasis. However, the underlying mechanism is unclear. In this study, we established Skp2-overexpressing stable transfectants from A549 human lung cancer cells. We found that these stable transfectants exhibited increased migratory and invasive abilities. In addition, expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was up-regulated. Enzymatic assay and gelatin zymography confirmed the increase of MMP-2 and MMP-9 activity and neutralization of these two MMPs by antibodies reduced cell invasion. Our results also revealed that Sp1 was involved in the induction of MMP-2 and MMP-9 by Skp2 because treatment of mithramycin or knockdown of Sp1 by small interference RNA attenuated their expressions. Collectively, we provide the first evidence that up-regulation of MMP-2 and MMP-9 is one of the mechanisms by which Skp2 promotes cell invasion. 2009 Elsevier Ireland Ltd. All rights reserved.