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  • Title: Paired box 8 suppresses tumor angiogenesis and metastasis in gastric cancer through repression of FOXM1 via induction of microRNA-612.
    Author: Wang L, Bo X, Zheng Q, Ge W, Liu Y, Li B.
    Journal: J Exp Clin Cancer Res; 2018 Jul 18; 37(1):159. PubMed ID: 30021604.
    Abstract:
    BACKGROUND: Paired box 8 (PAX8) has been documented to be downregulated in gastric cancer. However, its biological function in this malignancy is poorly understood. METHODS: In the present work, we investigated the effects of PAX8 overexpression and knockdown on the aggressive phenotype of gastric cancer cells. We further checked the involvement of forkhead box M1 (FOXM1), a ubiquitously expressed oncogene that can facilitate gastric cancer progression, in the action of PAX8. RESULTS: Ectopic expression of PAX8 blocked the migration and invasion of both AGS and SGC-7901 cells, but had no effect on cell proliferation. Conversely, knockdown of PAX8 enhanced gastric cancer cell migration and invasion. PAX8 overexpression inhibited epithelial-mesenchymal transition (EMT) and pro-angiogenic activity of gastric cancer cells. Mechanistically, PAX8 overexpression downregulated FOXM1 by stimulating microRNA (miR)-612 expression. Ectopic expression of miR-612 recapitulated the effect of PAX8 overexpression on gastric cancer cells, causing an inhibition of migration, invasion, EMT, and angiogenesis. Knockdown of miR-612 or overexpression of FOXM1 significantly reversed the tumor-suppressive activity of PAX8. In vivo studies further demonstrated that PAX8 overexpression restrained tumor angiogenesis and metastasis in nude mice, which was accompanied by increased expression of miR-612 and decreased expression of FOXM1. CONCLUSIONS: PAX8 exerts a tumor-suppressive effect against gastric cancer cells, largely through induction of miR-612 and repression of FOXM1. Therefore, restoration of PAX8 expression may offer therapeutic benefits in the treatment of gastric cancer.
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