Abstract 851P
Background
Aberrantly activated Wnt signaling is implicated in cancer progression and metastasis of many cancer entities. Platelet-activating factor (PAF), a potent inflammatory mediator, also contributes to tumorigenesis and invasiveness. However, the role of its degradation enzyme platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer (OC) carcinogenesis remains unclear. This study analyzes the functional impact of PAF-AH on BRCA1 mutant 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 moving capacity of BRCA1 mutant OC cells after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry.
Results
In an established OC collective, 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, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7 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.
Conclusions
Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact on BRCA1 mutant OC. We show for the first time 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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Brigitte und Dr. Konstanze Wegener-Stiftung.
Disclosure
A. Hester: Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: Pfizer. A. Burges: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Clovis. S. Mahner: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Medac; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Clovis; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: PharmaMar; Honoraria (self), Advisory/Consultancy: Sensor Kinesis; Honoraria (self), Advisory/Consultancy: Teva. F. Trillsch: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: PharmaMar; Honoraria (self), Advisory/Consultancy: Medan. All other authors have declared no conflicts of interest.