Abstract | BACKGROUND: METHODOLOGY AND PRINCIPAL FINDINGS: In this study, gene expression profiling was used to examine LPA-mediated transcription by exogenously adding LPA to human epithelial ovarian cancer cells for 24 h to mimic long-term stimulation in the tumor microenvironment. The resultant transcriptional profile comprised a 39-gene signature that closely correlated to serous epithelial ovarian carcinoma. Hierarchical clustering of ovarian cancer patient specimens demonstrated that the signature is associated with worsened prognosis. Patients with LPA-signature-positive ovarian tumors have reduced disease-specific and progression-free survival times. They have a higher frequency of stage IIIc serous carcinoma and a greater proportion is deceased. Among the 39-gene signature, a group of seven genes associated with cell adhesion recapitulated the results. Out of those seven, claudin-1, an adhesion molecule and phenotypic epithelial marker, is the only independent biomarker of serous epithelial ovarian carcinoma. Knockdown of claudin-1 expression in ovarian cancer cells reduces LPA-mediated cellular adhesion, enhances suspended cells and reduces LPA-mediated migration. CONCLUSIONS: The data suggest that transcriptional events mediated by LPA in the tumor microenvironment influence tumor progression through modulation of cell adhesion molecules like claudin-1 and, for the first time, report an LPA-mediated expression signature in ovarian cancer that predicts a worse prognosis.
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Authors | Mandi M Murph, Wenbin Liu, Shuangxing Yu, Yiling Lu, Hassan Hall, Bryan T Hennessy, John Lahad, Marci Schaner, Aslaug Helland, Gunnar Kristensen, Anne-Lise Børresen-Dale, Gordon B Mills |
Journal | PloS one
(PLoS One)
Vol. 4
Issue 5
Pg. e5583
( 2009)
ISSN: 1932-6203 [Electronic] United States |
PMID | 19440550
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- CLDN1 protein, human
- Claudin-1
- Lysophospholipids
- Membrane Proteins
- lysophosphatidic acid
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Topics |
- Blotting, Western
- Cell Adhesion
(genetics, physiology)
- Cell Line, Tumor
- Cell Proliferation
- Cell Survival
(genetics, physiology)
- Claudin-1
- Cluster Analysis
- Female
- Gene Expression Regulation, Neoplastic
(genetics)
- Humans
- Lysophospholipids
(pharmacology)
- Membrane Proteins
(genetics)
- Oligonucleotide Array Sequence Analysis
- Ovarian Neoplasms
(metabolism)
- Polymerase Chain Reaction
- Transcription, Genetic
(drug effects, genetics)
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