PLA2G7/PAF-AH as protective factor and potential negative regulator of the Wnt signaling pathway in BRCA1 mutant ovarian cancer

Background Platelet-activating factor (PAF) contributes to tumorigenesis and invasiveness. This study analyzes the functional impact of its degradation enzyme platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) on BRCA1 mutant ovarian cancer (OC) biology and its association with the Wnt signaling pathway.

Methods PAF-AH, pGSK3β and β-catenin expression was analyzed in 156 OC specimens by immunohistochemistry. Furthermore, PAF-AH expression was investigated in OC tissue and serum of BRCA1 mutation carriers. In-vitro experiments were performed to assess cell viability, proliferation and motility of BRCA1 mutant OC cells after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry.

Results We identified PAF-AH as an independent positive prognostic factor for overall survival. PAF-AH correlates strongly with the Wnt signaling proteins pGSK3β and β-catenin. Particular high levels of PAF-AH were found in tumor tissue and 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 OC cell line UWB1.289. Functional assays showed enhanced viability, proliferation and motility of UWB1.289 when PAF-AH was downregulated. By PLA2G7 silencing the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one.

Conclusion Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact on BRCA1 mutant OC and that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. A potential use of PAF-AH as biomarker for patients with BRCA1 negative OC should be explored.

Publikationsverlauf

Artikel online veröffentlicht:
07. Oktober 2020