title: Augmented Growth Hormone Secretion and Stat3 Phosphorylation in an Aryl Hydrocarbon Receptor Interacting Protein (AIP)-Disrupted Somatotroph Cell Line.
abstract: Aryl hydrocarbon receptor interacting protein (AIP) is thought to be a tumor suppressor gene, as indicated by a mutational analysis of pituitary somatotroph adenomas. However, the physiological significance of AIP inactivation in somatotroph cells remains unclear. Using CRISPR/Cas9, we identified a GH3 cell clone (termed GH3-FTY) in which Aip was genetically disrupted, and subsequently investigated its character with respect to growth hormone (Gh) synthesis and proliferation. Compared with GH3, GH3-FTY cells showed remarkably increased Gh production and a slight increase in cell proliferation. Gh-induced Stat3 phosphorylation is known to be a mechanism of Gh oversecretion in GH3. Interestingly, phosphorylated-Stat3 expression in GH3-FTY cells was increased more compared with GH3 cells, suggesting a stronger drive for this mechanism in GH3-FTY. The phenotypes of GH3-FTY concerning Gh overproduction, cell proliferation, and increased Stat3 phosphorylation were significantly reversed by the exogenous expression of Aip. GH3-FTY cells were less sensitive to somatostatin than GH3 cells in the suppression of cell proliferation, which might be associated with the reduced expression of somatostatin receptor type 2. GH3-FTY xenografts in BALB/c nude mice (GH3-FTY mice) formed more mitotic somatotroph tumors than GH3 xenografts (GH3 mice), as also evidenced by increased Ki67 scores. GH3-FTY mice were also much larger and had significantly higher plasma Gh levels than GH3 mice. Furthermore, GH3-FTY mice showed relative insulin resistance compared with GH3 mice. In conclusion, we established a somatotroph cell line, GH3-FTY, which possessed prominent Gh secretion and mitotic features associated with the disruption of Aip.
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.|Department of Bioregulatory Science of Life-related Diseases, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hamaguchi
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kawanami
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.|Department of Bioregulatory Science of Life-related Diseases, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomiyama
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.|Department of Bioregulatory Science of Life-related Diseases, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D020868:Gene Silencing; D013006:Growth Hormone / Q000378:metabolism*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D052683:Somatotrophs / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D015854:Up-Regulation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D050796:STAT3 Transcription Factor; C103265:aryl hydrocarbon receptor-interacting protein; D013006:Growth Hormone