IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis
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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.
KeywordsIGF-I IGF1R inhibitor ERβ Aromatase IGF1R/PI3K/AKT pathway Endometriosis
We appreciate Prof. Yu Qi and Prof. Ding-Fang Bu for their generous advices to the study. This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81270674) and the Natural Science Foundation of Beijing, China (Grant No.7132204).
Compliance to ethical standards
The cell experimental procedures were approved by the institutional review board of the First Hospital of Peking University (No. 2014 and No. 2014), and signed informed consents for use of the samples were obtained from each patient. The First Hospital of Peking University Animal Care Committee approved the use of mice for this study (No. J201403).
Conflict of interest
The authors declare that they have no competing interests.
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