title: 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.
authors.affiliation: Department of Pathology, Taizhou Central Hospital of Taizhou Enze Medical Group, Hongsheng Lu, 999 Donghai Road, 318000, Taizhou, Zhejiang, China, luhongsheng00@163.com.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Lu
authors.forename: Xuequan
authors.initials: X
authors.lastname: Cao
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Sun
authors.forename: Guangmin
authors.initials: G
authors.lastname: Fan
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Siling
authors.initials: S
authors.lastname: Wang
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9