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

Abstract 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 enh...

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Bibliographic Details
Published in:Cancer letters 2010-02, Vol.288 (2), p.156-161
Main Authors: Hung, Wen-Chun, Tseng, Wei-Lung, Shiea, Jentaie, Chang, Hui-Chiu
Format: Article
Language:English
Subjects:
Angiogenesis
Binding sites
Cell growth
Cell invasion
Cell Line, Tumor
Cell Movement
Cyclin-dependent kinases
Gene expression
Hematology, Oncology and Palliative Medicine
Humans
Kinases
Lung cancer
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Matrix metalloproteinases
Medical research
Neoplasm Invasiveness
Plicamycin - pharmacology
Proteins
RNA Interference
S-Phase Kinase-Associated Proteins - genetics
S-Phase Kinase-Associated Proteins - metabolism
Skp2
Sp1
Sp1 Transcription Factor - metabolism
Studies
Time Factors
Transfection
Tumorigenesis
Up-Regulation
Vascular endothelial growth factor
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Summary:Abstract 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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2009.06.032