title: STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion.
abstract: Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. GH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jiao
authors.forename: Renzhi
authors.initials: R
authors.lastname: Wang
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D021581:Active Transport, Cell Nucleus; D000236:Adenoma / Q000235:genetics / Q000378:metabolism*; D000636:Aminosalicylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D013006:Growth Hormone / Q000235:genetics; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism*; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011388:Prolactin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity; D015854:Up-Regulation
chemical_list: D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C520337:NSC 74859; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019382:Human Growth Hormone; D011388:Prolactin; D013006:Growth Hormone