<i>Gsp</i> mutation in acromegaly and its influence on <scp>TRH</scp>‐induced paradoxical <scp>GH</scp> response

Goto, Yuko; Kinoshita, Manabu; Oshino, Satoru; Arita, Hideyuki; Kitamura, Tatsuya; Otsuki, Michio; Shimomura, Iichiro; Yoshimine, Toshiki; Saitoh, Youichi

doi:10.1111/cen.12336

Cited by 6 publications

(9 citation statements)

References 29 publications

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“…A number of studies have been conducted to investigate the association between gsp oncogenes and clinical characteristics of patients with GH-secreting pituitary tumor (8,11,12,(17)(18)(19). The majority of the observations suggested that gsp-positive tumors indicated an increased secretory activity and reduced size, compared with gsp-negative tumors (9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

“…DNA was extracted and isolated from the frozen 25 GH-secreting tumor tissues with a DNA minikit (Qiagen GmbH, Hilden, Germany), according to the manufacturer's protocol. PCR amplification of exons 8 and 9, including codons 201 and 227, respectively, which are sites for G-protein α subunit (Gsα) mutations, was performed on human genomic DNA with oligonucleotide primers, as previously described (12). Each of the 50 µl PCR reaction mixes contained 2 µl DNA solution isolated from glass slides, 5 units of Taq DNA-Polymerase (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) and 20 pmol of each primer.…”

Section: Meg3 Is Associated With Gsp Oncogene Regulation Of Growth Homentioning

confidence: 99%

“…Maternally expressed gene 3 (MEG3) is a maternally imprinted gene encoding a long non-coding RNA that suppresses tumor cell proliferation (12,13). MEG3 is highly expressed in GH-secreting pituitary tumors, but not in clinically non-functioning pituitary tumors (14).…”

Section: Introductionmentioning

confidence: 99%

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MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH‑secreting adenomas

et al. 2019

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Overactivation of the Gs-mediated pathway by mutations of the G-protein α subunit (Gsα), a gsp oncogene, results in increased growth hormone (GH) hypersecretion and reduced tumor volume in patients with GH-secreting pituitary tumors. However, the mechanism underlying the clinical characteristics of gsp oncogene requires further investigation. Cyclic adenosine monophosphate-responsive element binding (CREB), as a downstream target gene of gsp oncogene, is implicated in activating maternally expressed gene 3 (MEG3). The present study proposes that gsp oncogene mediates MEG3-regulating GH hypersecretion, resulting in the small tumor size of GH-secreting tumors. Therefore, the present study detected Gsα mutations by polymerase chain reaction in GH-secreting tumors, and revealed that Gsα mutations were observed in 7/25 (28%) GH-secreting tumors. Gsp-positive tumors indicated significantly increased levels of phosphorylated p-CREB (P<0.0001) and MEG3 (P=0.039), compared with gsp-negative tumors. The results indicated that MEG3 levels were positively correlated with GH and IGF-1 levels, and negatively correlated with the tumor volume of GH-secreting tumors. The group with gsp-positive or with high MEG3 expression indicated a significantly reduced proportion of invasiveness and lower Ki-67 index, compared with the gsp-negative or low MEG3 expression group. In conclusion, gsp oncogene may mediate MEG3 by promoting GH hypersecretion, resulting in smaller tumors, as well as suppressing proliferation and invasiveness of GH-secreting pituitary tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Meg3 Is Associated With Gsp Oncogene Regulation Of Growth Homentioning

confidence: 99%

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MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH‑secreting adenomas

et al. 2019

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“…Genomic DNA was extracted from 44 GHPA and 10 NFPA tissues using a DNA miniprep kit according to the manufacturer's protocol (Qiagen GmbH, Hilden, Germany). The underlying point mutations in the GNAS gene have been reported in tumor specimens were CGT-to-TGT mutation at codon 201 (Arg201Cys) and CAG-to-CTG mutation at codon 227 (Gln227Leu) (Goto et al, 2014). PCR ampli cation of codon 201 and 227 was performed using a Taq DNAPolymerase (TTH Biotools Madrid, Spain) as previously described (Goto et al, 2014).…”

Section: Detection Of Mutations In the Gnas Genementioning

confidence: 99%

“…It has been well-demonstrated that mutations found in the GNAS gene, encoding α subunit of the stimulatory G protein, were detected in around 40% of GHPA (Goto et al, 2014, Hayward et al, 2001. The functional studies suggested that the GNAS mutations lead to the constitutive activation of adenylyl cyclase (AC), thereby inducing the cyclic AMP (cAMP) signaling pathway in pituitary tumors (Lania et al, 2012, Mantovani et al, 2010.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the GNAS Gene Prevent the Cell Invasion by Activating the MEG3/Wnt/β-catenin Axia in Growth Hormone-secreting Pituitary Adenoma

Tang¹,

Zhong

Zhu

et al. 2021

Preprint

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Approximately 30–40% of growth hormone-secreting pituitary adenoma (GHPA) harbor somatic mutations in the GNAS (α subunit of the stimulatory G protein) gene. However, the latent functional role of the mutations and relative molecular mechanism in GHPA remain unknown. The GNAS gene mutations were detected in GHPAs using a standard PCR-sequencing procedure. The mutation-associated MEG3 expression was measured by RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Alterations in mRNA profiles in the MEG3-overexpressed cells were analyzed by RNA-seq. The cell invasion ability was measured using a Transwell assay, and the EMT-associated proteins were quantified by immunofluorescence and western blot. Finally, a tumor cell xenograft mouse model was applied to verify the effect of MEG3 on tumor growth and invasiveness. The percentage of invasive tumors was significantly declined in GNAS-mutated GHPA tumors with the GNAS mutations compared to those tumors with the wild-type of GNAS. Consistently, the GH3 cell invasion capacity was decreased by expressing the mutant GNAS. MEG3 is uniquely expressed at high levels in GHPA harboring the mutated GNAS gene. Accordingly, the upregulation of MEG3 resulted in inhibiting cell invasion; and vice versa, the downregulation of MEG3 led to enhancing cell invasion. Mechanistically, the high level of MEG3 in mutated GNAS cells prevented the cell invasion via inactivation of the Wnt/β-catenin signaling pathway, which was further validated in vivo. The GNAS mutations inhibit the invasiveness of GHPA cells via inactivation of the MEG3/Wnt/β-catenin signaling pathway.

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Aberrant hormone receptors regulate a wide spectrum of endocrine tumors

Lacroix,

Bourdeau,

Chasseloup

et al. 2024

The Lancet Diabetes & Endocrinology

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Gsp mutation in acromegaly and its influence on TRH‐induced paradoxical GH response

Cited by 6 publications

References 29 publications

MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH‑secreting adenomas

MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH‑secreting adenomas

Mutations in the GNAS Gene Prevent the Cell Invasion by Activating the MEG3/Wnt/β-catenin Axia in Growth Hormone-secreting Pituitary Adenoma

Aberrant hormone receptors regulate a wide spectrum of endocrine tumors

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