STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

The Journal of Clinical Investigation
Cuiqi ZhouShlomo Melmed

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 nuclea...Continue Reading

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Citations

Jun 9, 2016·Endocrine-related Cancer·Thomas CunyAnne Barlier
Oct 11, 2016·Molecular and Cellular Endocrinology·Gabriela CarrenoJuan Pedro Martinez-Barbera
Apr 6, 2017·Journal of Cell Communication and Signaling·María Florencia GottardoAdriana Seilicovich
Jul 5, 2019·Journal of Cellular Biochemistry·Ajda Coker-GurkanNarcin Palavan-Unsal
Jun 22, 2019·BMC Molecular and Cell Biology·Yangyang HanMin Cheng
Dec 3, 2016·Oncotarget·Melanie SapochnikEduardo Arzt
Jul 14, 2020·Journal of Neuroendocrinology·Melody L Allensworth-JamesGwen V Childs
Mar 23, 2019·Nature Reviews. Disease Primers·Annamaria ColaoRosario Pivonello
Feb 8, 2019·JCI Insight·Vera ChesnokovaShlomo Melmed
Jan 13, 2021·Endocrine Pathology·Sylvia L AsaShereen Ezzat
Feb 13, 2021·Frontiers in Endocrinology·Mengqi ChangRenzhi Wang
Apr 2, 2021·Frontiers in Endocrinology·Joan GilManel Puig-Domingo
Sep 2, 2021·The Journal of Clinical Endocrinology and Metabolism·Cuiqi ZhouShlomo Melmed

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Methods Mentioned

BETA
ChIP
PCR
nuclear translocation
xenografts
surgical resection
transfection
Assay
ELISA
FACS

Software Mentioned

Genomatix MatInspector
SPSS10

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