| 英文摘要 |
Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptorα(RORα) is related to cancer development and progression. We previously discovered that diallyl disulfide (DADS), one of active components of garlic, increases RORαexpression in gastric cancer (GC) cells by using proteomic approaches. This study revealed that DADS treatment resulted in reducing Wnt1,β-catenin, TCF-4, intranuclearβ-catenin and p-β-catenin levels in GC cells, concomitant with the decreased expression ofβ-catenin target genes (Axin, c-Jun, and c-Myc). RORαoverexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo. However, knockdown of RORαattenuated these effects of DADS. Intriguingly, DADS induced an increase in the binding of RORαtoβ-catenin, which may lead to reduction ofβ-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affectβ-catenin target gene expression for that the opposite results were observed in DADS-treated RORαknockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, restricting epithelial‑mesenchymal transition (EMT), migration, and invasion. These effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORαenhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion. |
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