title: IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China.
authors.forename: Ying-Fang
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi'anmen Street, 100034, Beijing, China. 13601038626@163.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xue
mesh_terms: D000328:Adult; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D001141:Aromatase; D017362:Cyclic AMP Response Element-Binding Protein; D047629:Estrogen Receptor beta; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C115163:CREB1 protein, human; C000600034:ESR2 protein, human; C000597236:IGF1R protein, human; C561410:CYP19A1 protein, human
keywords: Aromatase; ERβ; Endometriosis; IGF-I; IGF1R inhibitor; IGF1R/PI3K/AKT pathway