IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis

Autor: Cheng Zeng, Ling Yin, Xiao-Lan Yu, Pei-Li Wu, Qing Xue, Ying-Fang Zhou, Yan Zhou, Xin Li
Rok vydání: 2015
Předmět:
0301 basic medicine
Adult
Transcriptional Activation
medicine.medical_specialty
Proto-Oncogene Proteins c-jun
Endometriosis
Mice
Nude
CREB
Receptor
IGF Type 1
03 medical and health sciences
Mice
Phosphatidylinositol 3-Kinases
Young Adult
0302 clinical medicine
Aromatase
Internal medicine
Drug Discovery
medicine
Animals
Estrogen Receptor beta
Humans
Insulin-Like Growth Factor I
Cyclic AMP Response Element-Binding Protein
Promoter Regions
Genetic
Protein kinase B
Genetics (clinical)
PI3K/AKT/mTOR pathway
Estrogen receptor beta
Cells
Cultured
Insulin-like growth factor 1 receptor
030219 obstetrics & reproductive medicine
biology
Chemistry
Receptors
Somatomedin
030104 developmental biology
Endocrinology
Enzyme Induction
biology.protein
Cancer research
Molecular Medicine
Female
Signal transduction
Stromal Cells
Chromatin immunoprecipitation
Protein Processing
Post-Translational
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Journal of molecular medicine (Berlin, Germany). 94(8)
ISSN: 1432-1440
Popis: Estrogen receptor beta (ERβ, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERβ and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERβ and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERβ and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERβ and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERβ and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug.Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERβ and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.
Databáze: OpenAIRE
Externí odkaz: