Dataset Information

Platelet-activating factor induces the stemness of ovarian cancer cells via the PAF/PAFR signaling pathway.

ABSTRACT:

Background

Cancer stem cells (CSCs) play an important role in tumor recurrence, metastasis, and chemoresistance. CSCs can shift between non-CSC and CSC states in certain tumor microenvironments. The mechanisms of this shift are not well understood. We previously demonstrated that platelet-activating factor (PAF), a lipid mediator of inflammation in the tumor microenvironment, can promote ovarian cancer progression and induce chemoresistance via PAF/PAFR-mediated inflammatory signaling pathways. Here, we investigated the role of PAF/PAFR signaling in the stemness of ovarian cancer cell.

Methods

The effects of PAF and PAFR antagonists on the stemness of SKOV3 and A2780 cells were evaluated using sphere-formation assays, FACS analysis and real-time PCR in vitro and a SKOV3 tumor-formation experiment in nude mice in vivo. The potential mechanism of the PAF effect on the stemness of ovarian cancer cells was evaluated by human cytokine antibody microarray analysis.

Results

PAF can promote spheroid formation and inhibit the transition of quiescent ovarian cancer cells into the cell cycle. The percentage of cancer stem cells increased significantly, and the expression of stemness genes increased in PAF-treated group. These effects could be blocked by PAFR inhibitors. Ginkgolide B (GB) inhibited tumor growth and decreased the CSC percentage in vivo. Human cytokine antibody microarray analysis showed that some stemness-maintaining proteins increased in PAF-treated group.

Conclusion

Our results suggest that PAF can regulate the stemness of ovarian cancer cells through the PAF/PAFR pathway, suggesting a new target for the treatment of ovarian cancer.

SUBMITTER: Gao T

PROVIDER: S-EPMC7724322 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Platelet-activating factor induces the stemness of ovarian cancer cells via the PAF/PAFR signaling pathway.

Gao Tong T Zhao Ran R Yao Liangqing L Xu Congjian C Cong Qing Q Jiang Wei W

American journal of translational research 20201115 11

<h4>Background</h4>Cancer stem cells (CSCs) play an important role in tumor recurrence, metastasis, and chemoresistance. CSCs can shift between non-CSC and CSC states in certain tumor microenvironments. The mechanisms of this shift are not well understood. We previously demonstrated that platelet-activating factor (PAF), a lipid mediator of inflammation in the tumor microenvironment, can promote ovarian cancer progression and induce chemoresistance via PAF/PAFR-mediated inflammatory signaling pa ...[more]

PMID: 33312364

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Project description:Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3β, and β-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3β (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and β-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/β-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored.

Dataset Information

Platelet-activating factor induces the stemness of ovarian cancer cells via the PAF/PAFR signaling pathway.

Background

Methods

Results

Conclusion

Publications

Platelet-activating factor induces the stemness of ovarian cancer cells via the PAF/PAFR signaling pathway.

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