The Protein Kinase A Pathway-Regulated Transcriptome of Endometrial Stromal Fibroblasts Reveals Compromised Differentiation and Persistent Proliferative Potential in Endometriosis
| Autor: | Lusine Aghajanova, Linda C. Giudice, James L. Weeks, Francisco J. Esteban, José A. Horcajadas, Marco Conti, Camran N. Nezhat |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
medicine.medical_specialty MAP Kinase Signaling System Cellular differentiation Endometriosis Biology Endometrium Article Young Adult Endocrinology Cyclins Internal medicine medicine Humans Protein kinase A Cell Proliferation Cyclin Extracellular Matrix Proteins Phosphoric Diester Hydrolases Kinase Cell growth Gene Expression Profiling Cell Cycle Decidualization Cell Differentiation Forkhead Transcription Factors Fibroblasts Middle Aged Cell cycle Cyclic AMP-Dependent Protein Kinases Wnt Proteins Cytoskeletal Proteins medicine.anatomical_structure Gene Expression Regulation Case-Control Studies Female |
| Zdroj: | Endocrinology. 151:1341-1355 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2009-0923 |
| Popis: | Intrinsic abnormalities in transplanted eutopic endometrium are believed to contribute to the pathogenesis of pelvic endometriosis. Herein we investigated transcriptomic differences in human endometrial stromal fibroblasts (hESFs) from women with (hESF(endo)) vs. without (hESF(nonendo)) endometriosis, in response to activation of the protein kinase A (PKA) pathway with 8-bromoadenosine-cAMP (8-Br-cAMP). hESF(nonendo) (n = 4) and hESF(endo) (n = 4) were isolated from eutopic endometrium and treated +/- 0.5 mm 8-Br-cAMP for 96 h. Purified total RNA was subjected to microarray analysis using the whole-genome Gene 1.0 ST Affymetrix platform. A total of 691 genes were regulated in cAMP-treated hESF(nonendo) vs. 158 genes in hESF(endo), suggesting a blunted response to cAMP/PKA pathway activation in women with disease. Real-time PCR and ELISA validated the decreased expression of decidualization markers in hESF(endo) compared with hESF(nonendo). In the absence of disease, 8-Br-cAMP down-regulated progression through the cell cycle via a decrease in cyclin D1, cyclin-dependent kinase 6, and cell division cycle 2 and an increase in cyclin-dependent kinase inhibitor 1A. However, cell cycle components in hESF(endo) were not responsive to 8-Br-cAMP, resulting in persistence of a proliferative phenotype. hESF(endo) treated with 8-Br-cAMP exhibited altered expression of immune response, extracellular matrix, cytoskeleton, and apoptosis genes. Changes in phosphodiesterase expression and activity were not different among experimental groups. These data support that eutopic hESF(endo) with increased proliferative potential can seed the pelvic cavity via retrograde menstruation and promote establishment, survival, and proliferation of endometriosis lesions, independent of hydrolysis of cAMP and likely due to an inherent abnormality in the PKA pathway. |
| Databáze: | OpenAIRE |
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