Abstract
ObjectivesIt is essential to understand the molecular basis of ovarian cancer etiology and tumor development to provide more effective preventive and therapeutic approaches to reduce mortality. Particularly, the molecular targets and pathways involved in early malignant transformation are still not clear. Pro-inflammatory lipids and pathways have been reported to play significant roles in ovarian cancer progression and metastasis. The major objective of this study was to explore and determine whether platelet activating factor (PAF) and receptor associated networking pathways might significantly induce malignant potential in BRCA1-mutant at-risk epithelial cells.MethodsBRCA1-mutant ovarian epithelial cell lines including (HOSE-636, HOSE-642), BRCA1-mutant ovarian cancer cell (UWB1.289), wild type normal ovarian epithelial cell (HOSE-E6E7) and cancerous cell line (OVCA429), and the non-malignant BRCA1-mutant distal fallopian tube (fimbria) tissue specimens were used in this study. Mutation analysis, kinase microarray, western blot, immune staining, co-immune precipitation, cell cycle, apoptosis, proliferation and bioinformatic pathway analysis were applied.ResultsWe found that PAF, as a potent pro-inflammatory mediator, induced significant anti-apoptotic effect in BRCA1-mutant ovarian surface epithelial cells, but not in wild type HOSE cells. With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM PAF treatment only in BRCA1-mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSE-E6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that elevated PAFR expression is associated with protein-protein interactions of PAFR-FAK and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells.ConclusionPrevious studies showed that potent inflammatory lipid mediators such as PAF and its receptor (PAFR) significantly contribute to cancer progression and metastasis. Our findings suggest that these potent inflammatory lipids and receptor pathways are significantly involved in the early malignant transformation through PAFR-FAK-STAT1 networking and to block apoptosis pathway in BRCA1 dysfunctional at-risk ovarian epithelium.
Highlights
The combination of mutation and aberrant expression of tumor suppressor genes is critical in cancer susceptibility and tumor progression
With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM platelet activating factor (PAF) treatment only in BRCA1mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSEE6E7) or malignant (OVCA429) ovarian epithelial cells
Co-immune precipitation revealed that elevated PAF and its receptor (PAFR) expression is associated with protein-protein interactions of PAFR-Focal Adhesion Kinase (FAK) and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells
Summary
The combination of mutation and aberrant expression of tumor suppressor genes is critical in cancer susceptibility and tumor progression. Previous publications indicate that a BRCA1 mutation is associated with cancer progression through pathways of cell proliferation [5], differentiation [6], and apoptosis [7]. It is known that loss of BRCA1 function may activate JAK-STAT pathways and stimulate cell proliferation in breast, prostate, lung and ovarian cancer [8,9]. It is still unclear what molecular mechanisms and targets characterize the early molecular events of malignant transformation
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