Abstract
Ovarian cancer is the most lethal gynecological malignancy due to its high metastatic ability. Epithelial-mesenchymal transition (EMT) is essential during both follicular rupture and epithelium regeneration. However, it may also accelerate the progression of ovarian carcinomas. Experimental studies have found that 1α,25-dihydroxyvitamin-D3 [1α,25(OH)2D3] can inhibit the proliferation of ovarian cancer cells. In this study, we investigated whether 1α,25(OH)2D3 could inhibit the migration of ovarian cancer cells via regulating EMT. We established a model of transient transforming growth factor-β1(TGF-β1)-induced EMT in human ovarian adenocarcinoma cell line SKOV-3 cells. Results showed that, compared with control, 1α,25(OH)2D3 not only inhibited the migration and the invasion of SKOV-3 cells, but also promoted the acquisition of an epithelial phenotype of SKOV-3 cells treated with TGF-β1. We discovered that 1α,25(OH)2D3 increased the expression of epithelial marker E-cadherin and decreased the level of mesenchymal marker, Vimentin, which was associated with the elevated expression of VDR. Moreover, 1α,25(OH)2D3 reduced the expression level of transcription factors of EMT, such as slug, snail, and β-catenin. These results indicate that 1α,25(OH)2D3 suppresses the migration and invasion of ovarian cancer cells by inhibiting EMT, implying that 1α,25(OH)2D3 might be a potential therapeutic agent for the treatment of ovarian cancer.
Highlights
Ovarian cancer has the highest fatality rate among women, primarily due to advanced stage at diagnosis, the lack of effective therapies for late-stage, and the replase after chemotherapy and surgery, which result in poor overall survival for the patients [1]
TRh).eTrehseurltessfurlotms frboomth ibmotmhuinmomfluuonroefslcueonrceescaenndceWeasntdernWbelsottetrinngbslhoottwinegd tshhaotwtheedetxhpartestshioeneoxfpVreDssRioinn SoKfOVVD-3Rceilnls SoKnOlyVt-r3eacteeldlsboynTlyGFtr-eβa1tewdabsyloTwGeFr -tβh1anwthasatloinwceerlltshtarenattehdatwinithcethlles ctoremabteidnawtioitnhotfh1eαc,o25m(ObiHna)2tDio3naonfd 1α,25(OH)2D3 and TGF-β1 (Figure 4C,F, p < 0.05). These results showed that 1α,25(OH)2D3 inhibited the TGF-β1-induced Epithelial-mesenchymal transition (EMT) accompanied with increased expression of VDR in ovarian cancer cells
These findings demonstrated that vitamin D inhibited proliferation of ovarian cancer cells
Summary
Ovarian cancer has the highest fatality rate among women, primarily due to advanced stage at diagnosis, the lack of effective therapies for late-stage, and the replase after chemotherapy and surgery, which result in poor overall survival for the patients [1]. Epithelial-mesenchymal transition (EMT) is a reversible cellular process by which epithelial cells depolarize, lose cell–cell contacts, and gain a spindle-mesenchymal morphology. It is characterized by loss of epithelial morphology and cytoskeletal reorganization, rendering cells more migratory and invasive [2]. This process is essential for embryonic development and wound healing. Experimental studies suggest that 1α,25(OH)2D3, active metabolite of vitamin D, and its synthetic derivatives, protect against ovarian cancer, manifesting anti-proliferative and pro-apoptotic effects in ovarian cancer cell lines [6,7,8,9,10,11,12] and anti-tumorigenesis in animal models [13,14,15]. We found that TGF-β-induced EMT in ovarian cancer cells could be inhibited by 1α,25(OH)2D3
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