title: Downregulation of Skp2 inhibits the growth and metastasis of gastric cancer cells in vitro and in vivo.
abstract: S-phase kinase-associated protein-2 (Skp2) is overexpressed in human cancers and associated with poor prognosis. Skp2 acts as an oncogenic protein by enhancing cancer cell growth and tumor metastasis. The present study has demonstrated that small hairpin RNA (shRNA)-mediated downregulation of Skp2 markedly inhibits the viability, proliferation, colony formation, migration, invasion, and apoptosis of human gastric cancer MGC803 cells, which express a high level of Skp2. In contrast, Skp2 shRNA had only a slight effect on the above properties of BGC823 cells, which express a low level of Skp2. In accord, knockdown of Skp2 suppressed the ability of MGC803 cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors, by inhibiting cell proliferation and enhancing cell apoptosis. In contrast, overexpression of Skp2 promoted tumorigenesis of BGC823 cells in mice. Skp2 depletion induced cell cycle arrest in the G(1)/S phase by upregulating p27, p21, and p57 and downregulating cyclin E and cyclin-dependent kinase 2. Skp2 depletion also increased caspase-3 activity, impeded the ability of cells to form filopoidia and locomote, upregulated RECK (reversion-inducing cysteine-rich protein with kazal motifs), and downregulated matrix metalloproteinase (MMP)-2 and MMP-9 activity and expression. The results suggest that downregulating Skp2 warrants investigation as a promising strategy to treat gastric cancers that express high levels of Skp2.
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.forename: Fengjun
authors.initials: F
authors.lastname: Liu
authors.forename: Haiquan
authors.initials: H
authors.lastname: Qiao
authors.forename: Baoguo
authors.initials: B
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Xuwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Likun
authors.initials: L
authors.lastname: Han
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis; D015536:Down-Regulation; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation
chemical_list: C493964:CDKN1C protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; D058851:GPI-Linked Proteins; C115460:RECK protein, human; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9