title: Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Obstetrics and Gynecology Department, Peking University People's Hospital, Beijing, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Dale
authors.initials: D
authors.lastname: Edwards
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Barroilhet
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Rho
authors.forename: Lianjin
authors.initials: L
authors.lastname: Jin
authors.forename: Vanitha
authors.initials: V
authors.lastname: Seethappan
authors.forename: Allison
authors.initials: A
authors.lastname: Vitonis
authors.forename: Jianliu
authors.initials: J
authors.lastname: Wang
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.forename: Christopher
authors.initials: C
authors.lastname: Crum
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology*; D019398:Genes, BRCA1 / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012306:Risk; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C039351:platelet activating factor receptor; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human