|Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium|
|Zhang, Lifang1; Wang, Dan2; Jiang, Wei4; Edwards, Dale2; Qiu, Weiliang3; Barroilhet, Lisa M.2; Rho, Jung-Hyun3; Jin, Lianjin2; Seethappan, Vanitha2; Vitonis, Allison2; Wang, Jianliu1; Mok, Samuel C.5; Crum, Christopher6; Cramer, Daniel W.2; Ye, Bin2|
|刊名||REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY|
|WOS标题词||Science & Technology|
|类目[WOS]||Endocrinology & Metabolism ; Reproductive Biology|
|研究领域[WOS]||Endocrinology & Metabolism ; Reproductive Biology|
|关键词[WOS]||FOCAL-ADHESION KINASE ; GROWTH-FACTOR-RECEPTOR ; PROTEIN-COUPLED RECEPTORS ; TYROSINE PHOSPHORYLATION ; CANCER SUSCEPTIBILITY ; ENDOTHELIAL-CELLS ; BRCA1 MUTATIONS ; BREAST-CANCER ; STAT PROTEINS ; STEM-CELLS|
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 nonmalignant 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.
|项目编号||R21 (CA111949-01) ; R01 (CA054419-13) ; 1P50-CA105009-01|
|资助机构||National Cancer Institute ; Dana-Farber Cancer Center Starr Foundation ; ovarian cancer case-control study ; ovarian cancer SPORE ; China Scholarship Council (Lifang Zhang)|
|作者单位||1.Peking Univ, Peoples Hosp, Dept Obstet & Gynecol, Beijing 100871, Peoples R China|
2.Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA
3.Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA
4.Fudan Univ, Obstet & Gynecol Hosp, Shanghai 200011, Peoples R China
5.Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA
6.Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
|Zhang, Lifang,Wang, Dan,Jiang, Wei,et al. Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium[J]. REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY,2010,8.|
|APA||Zhang, Lifang.,Wang, Dan.,Jiang, Wei.,Edwards, Dale.,Qiu, Weiliang.,...&Ye, Bin.(2010).Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium.REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY,8.|
|MLA||Zhang, Lifang,et al."Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium".REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY 8(2010).|