Platelet-Activating Factor Acetylhydrolase Expression in BRCA1 Mutant Ovarian Cancer as a Protective Factor and Potential Negative Regulator of the Wnt Signaling Pathway

Abstract

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.

PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer

“…By functional assays in HCC1937 cells, we show that the loss of PAF-AH leads to cancer progression with enhanced viability, proliferation, and migration. This finding underlines its protective character which we have already shown for the BRCA1 mutant OC [31]. This effect might be mediated by an inhibition of the Wnt/β-catenin pathway.…”

“…Moreover, PAF is highly expressed in BC cells and positively regulates the Wnt signaling pathway as a cofactor of the β-catenin transcription complex [41,42]. Our previous results indicate a negative regulatory impact of PAF-AH on the Wnt/β-catenin signaling pathway in BRCA1 mutated OC [31]. PLA2G7 silencing in BRCA1 mutant OC cells reduced the expression of membranous β-catenin, but led to a strong upregulation of its nuclear expression.…”

“…On the other hand, there is evidence of reduced tumor growth and prolonged survival in mouse models of Kaposi's sarcoma and melanoma with PAF-AH overexpression [30]. Through our recent results, our team identified PAF-AH as an independent positive prognostic factor for overall survival in OC patients [31].…”

Investigating the potential mechanism of quercetin against cervical cancer

“…On the other hand, Liao et al discovered that high PLA2G7 protein level was associated with significantly longer OS than low protein level of PLA2G7 in ovarian cancer patients. The protective character of PLA2G7 was speculated to be mediated by negatively regulating the Wnt/β-catenin pathway [ 68 ]. Similarly, our analysis showed that PLA2G7 was associated with a better prognosis in CESC.…”

VCAM-1 complements CA-125 in detecting recurrent ovarian cancer

“…To date, many different biomarkers have been identified, including growth differentiation factor 15 (GDF-15), interleukin 6 (IL-6), Interleukin-6 receptor subunit alpha (IL-6 R alpha), vascular cell adhesion molecule 1 (VCAM-1), CD276 molecule (B7-H3), syndecan-1 (SDC1), and TEK receptor tyrosine kinase (Tie-2) for detection and monitoring of ovarian cancer [ 6 – 22 ]. Phospholipase A2 group VII (PLA2G7) was expressed in BRCA1 mutant ovarian cancer as a protective factor and potential negative regulator of the Wnt signalling pathway [ 23 ]. Some combinations of these biomarkers such as HE4, osteopontin (OPN), and GDF-15 along with CA-125 seem promising, but still lack of sufficient sensitivity or specificity for early detection of recurrent ovarian cancer [ 6 , 7 , 9 , 10 , 12 , 13 , 24 – 28 ].…”