Open Access

ARTICLE

GNAS mutations suppress cell invasion by activating MEG3 in growth hormone–secreting pituitary adenoma

CHAO TANG^1,#, CHUNYU ZHONG^2,#, JUNHAO ZHU¹, FENG YUAN¹, JIN YANG¹, YONG XU^3,*, CHIYUAN MA^1,3,4,5,*
1 Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
2 Department of Neurosurgery, Children’s Hospital of Nanjing Medical University, Nanjing, 210019, China
3 Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, China
4 Department of Neurosurgery, Jinling Hospital, Southern Medical University, Nanjing, 210002, China
5 Department of Neurosurgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, China
* Corresponding Author: YONG XU. Email: ; CHIYUAN MA. Email:

Oncology Research https://doi.org/10.32604/or.2024.046007

Received 14 September 2023; Accepted 08 December 2023; Published online 25 March 2024

Abstract

Approximately 30%–40% of growth hormone–secreting pituitary adenomas (GHPAs) harbor somatic activating mutations in GNAS (α subunit of stimulatory G protein). Mutations in GNAS are associated with clinical features of smaller and less invasive tumors. However, the role of GNAS mutations in the invasiveness of GHPAs is unclear. GNAS mutations were detected in GHPAs using a standard polymerase chain reaction (PCR) sequencing procedure. The expression of mutation-associated maternally expressed gene 3 (MEG3) was evaluated with RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Cell invasion ability was measured using a Transwell assay, and epithelial–mesenchymal transition (EMT)-associated proteins were quantified by immunofluorescence and western blotting. Finally, a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness. The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS. Consistently, the invasiveness of mutant GNAS-expressing GH3 cells decreased. MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS. Accordingly, MEG3 upregulation inhibited tumor cell invasion, and conversely, MEG3 downregulation increased tumor cell invasion. Mechanistically, GNAS mutations inhibit EMT in GHPAs. MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/β-catenin signaling pathway, which was further validated in vivo. Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/β-catenin signaling pathway.

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Keywords

GHPAs; GNAS mutation; MEG3; β-catenin; EMT

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