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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2010

Open Access 01-12-2010 | Research

Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium

Authors: Lifang Zhang, Dan Wang, Wei Jiang, Dale Edwards, Weiliang Qiu, Lisa M Barroilhet, Jung-hyun Rho, Lianjin Jin, Vanitha Seethappan, Allison Vitonis, Jianliu Wang, Samuel C Mok, Christopher Crum, Daniel W Cramer, Bin Ye

Published in: Reproductive Biology and Endocrinology | Issue 1/2010

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Abstract

Objectives

It 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.

Methods

BRCA1-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.

Results

We 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.

Conclusion

Previous 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.
Appendix
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Metadata
Title
Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium
Authors
Lifang Zhang
Dan Wang
Wei Jiang
Dale Edwards
Weiliang Qiu
Lisa M Barroilhet
Jung-hyun Rho
Lianjin Jin
Vanitha Seethappan
Allison Vitonis
Jianliu Wang
Samuel C Mok
Christopher Crum
Daniel W Cramer
Bin Ye
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2010
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-8-74

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