Activated Networking of Platelet Activating Factor Receptor and FAK/STAT1 Induces Malignant Potential in BRCA1-mutant At-risk Ovarian Epithelium

Overview

Journal Reprod Biol Endocrinol

Publisher Biomed Central

Specialties Endocrinology
Reproductive Medicine

Date 2010 Jun 26

PMID 20576130

Citations 13

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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

Liao Y, Badmann S, Kraus F, Topalov N, Mayr D, Kolben T Int J Mol Sci. 2023; 24(1).

PMID: 36614323 PMC: 9821466. DOI: 10.3390/ijms24010882.

The Platelet-Activating Factor Receptor's Association with the Outcome of Ovarian Cancer Patients and Its Experimental Inhibition by Rupatadine.

Deuster E, Hysenaj I, Kahaly M, Schmoeckel E, Mayr D, Beyer S Cells. 2021; 10(9).

PMID: 34571986 PMC: 8466210. DOI: 10.3390/cells10092337.

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

Liao Y, Badmann S, Kaltofen T, Mayr D, Schmoeckel E, Deuster E Biomedicines. 2021; 9(7).

PMID: 34206491 PMC: 8301368. DOI: 10.3390/biomedicines9070706.

Gene Expression Profiling in Ovaries and Association Analyses Reveal as a Candidate Gene for Sexual Maturity in Chickens.

Chen B, Liang G, Zhu X, Tan Y, Xu J, Wu H Animals (Basel). 2020; 10(2).

PMID: 31973127 PMC: 7071030. DOI: 10.3390/ani10020181.

Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer.

Tian X, Guan W, Zhang L, Sun W, Zhou D, Lin Q J Exp Clin Cancer Res. 2018; 37(1):103.

PMID: 29751820 PMC: 5948853. DOI: 10.1186/s13046-018-0773-8.

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