Dataset Information

Knockdown of CYP24A1 Aggravates 1?,25(OH)2D3-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT.

ABSTRACT: Epithelial-mesenchymal transition (EMT) bestows cancer cells with motile and invasive properties. But for ovarian tissues, EMT plays a physiological role in the postovulatory repair of ovary surface epithelial (OSE) cells. Accumulating data indicated that 1?,25(OH)2D3 decreased both the migration and invasion of various cancer cells by suppressing EMT. However, it remains unclear whether 1?,25(OH)2D3 inhibits the process of EMT during different stages of oncogenic transformation in mouse OSE (MOSE) cells. In present study, a spontaneous malignant transformation model of MOSE cells at three sequential stages (early, intermediate and late) was established in vitro first and then subjected to 1?,25(OH)2D3 treatment to investigate the effect of 1?,25(OH)2D3 on the oncogenic transformation of MOSE cells. We found that 1?,25(OH)2D3 significantly reduced the proliferation and invasion of late malignant transformed MOSE (M-L cells) cells by inhibiting EMT both in vitro and in vivo, but not in intermediate transformed (M-I) cells. Importantly, we found that the levels of CYP24A1 in M-I cells were dramatically higher than that in M-L cells following treatment with 1?,25(OH)2D3. Furthermore, we demonstrated that, in both M-I and M-L cells with CYP24A1 knockdown, 1?,25(OH)2D3 suppressed the proliferation and invasion, and reduced the expression of N-cadherin, Vimentin, ?-catenin and Snail. In addition, knockdown of CYP24A1 suppressed EMT by increasing E-cadherin while decreasing N-cadherin, Vimentin, ?-catenin and Snail. These findings provide support for inhibiting CYP24A1 as a potential approach to activate the vitamin D pathway in the prevention and therapy of ovarian cancer.

SUBMITTER: Wang P

PROVIDER: S-EPMC7403498 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Knockdown of CYP24A1 Aggravates 1α,25(OH)2D3-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT.

Wang Ping P Xu Jiming J You Weijing W Hou Yongfeng Y Wang Shuiliang S Ma Yujie Y Tan Jianming J Zhang Zengli Z Hu Wentao W Li Bingyan B

Frontiers in oncology 20200729

Epithelial-mesenchymal transition (EMT) bestows cancer cells with motile and invasive properties. But for ovarian tissues, EMT plays a physiological role in the postovulatory repair of ovary surface epithelial (OSE) cells. Accumulating data indicated that 1α,25(OH)2D3 decreased both the migration and invasion of various cancer cells by suppressing EMT. However, it remains unclear whether 1α,25(OH)2D3 inhibits the process of EMT during different stages ...[more]

PMID: 32850381

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Project description:Colorectal cancer (CRC) is a significant health burden especially among African Americans (AA). Epidemiological studies have correlated low serum vitamin D with CRC risk, and, while hypovitaminosis D is more common and more severe in AA, the mechanisms by which vitamin D modulates CRC risk and how these differ by race are not well understood. Active vitamin D (1α,25(OH)2D3) has chemoprotective effects primarily through transcriptional regulation of target genes in the colon. We hypothesized that transcriptional response to 1α,25(OH)2D3 differs between AA and European Americans (EA) irrespective of serum vitamin D and that regulatory variants could impact transcriptional response. We treated ex vivo colon cultures from 34 healthy subjects (16 AA and 18 EA) with 0.1μM 1α,25(OH)2D3 or vehicle control for 6h and performed genome-wide transcriptional profiling. We found 8 genes with significant differences in transcriptional response to 1α,25(OH)2D3 between AA and EA with definitive replication of inter-ethnic differences for uridine phosphorylase 1 (UPP1) and zinc finger-SWIM containing 4 (ZSWIM4). We performed expression quantitative trait loci (eQTL) mapping and identified response cis-eQTLs for ZSWIM4 as well as for histone deacetylase 3 (HDAC3), the latter of which showed a trend toward significant inter-ethnic differences in transcriptional response. Allele frequency differences of eQTLs for ZSWIM4 and HDAC3 accounted for observed transcriptional differences between populations. Taken together, our results demonstrate that transcriptional response to 1α,25(OH)2D3 differs between AA and EA independent of serum 25(OH)D levels. We provide evidence in support of a genetic regulatory mechanism underlying transcriptional differences between populations for ZSWIM4 and HDAC3. Further work is needed to elucidate how response eQTLs modify vitamin D response and whether genotype and/or transcriptional response correlate with chemopreventive effects. Relevant biomarkers, such as tissue-specific 1α,25(OH)2D3 transcriptional response, could identify individuals likely to benefit from vitamin D for CRC prevention as well as elucidate basic mechanisms underlying CRC disparities.

Dataset Information

Knockdown of CYP24A1 Aggravates 1?,25(OH)2D3-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT.

Publications

Knockdown of CYP24A1 Aggravates 1α,25(OH)<sub>2</sub>D<sub>3</sub>-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT.

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