Imbalance between MMP-2, 9 and TIMP-1 promote the invasion and metastasis of renal cell carcinoma via SKP2 signaling pathways.

Abstract

S-phase kinase-associated protein-2 (Skp2) is overexpressed in human cancers and acted as an oncogenic protein associated with poor prognosis by enhancing tumor metastasis. The present study has demonstrated that Skp2 overexpresses stable transfectants from 786-0 human renal 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 upregulated and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was downregulated. In contrast, RNA interference-mediated knockdown Skp2 expression suppressed the ability of ACHN cells to migratory and invasive. Skp2 depletion increased P27 and decreased cyclin E activity, and then induced cell cycle arrest in the G0/G1 phase. Skp2 depletion also downregulated MMP-2 and MMP-9, while upregulated the TIMP-1 activity and expression. The results suggest that Skp2 signaling pathways promoted the ability to metastasize, by stimulating cell proliferation and increasing the ratio of MMP-2 and MMP-9/TIMP-1. So, in conclusion, we provide the first evidence that the imbalance of MMP/TIMP, including upregulation of MMP-2 and MMP-9 and downregulation of TIMP-1, is one of the mechanisms by which Skp2 promotes cell invasion.