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

Approximately 30%–40%of growth hormone–secreting pituitary adenomas(GHPAs)harbor somatic activating mutations in GNAS(αsubunit 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 GNASexpressing 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.

Intra-abdominal ectopic bronchogenic cyst with a mucinous neoplasm harboring a GNAS mutation: A case report

BACKGROUND Bronchogenic cysts are congenital cysts caused by abnormal sprouting from the ventral foregut during fetal life.They usually occur in the mediastinum or lung,but there are very rare cases of ectopic bronchogenic cysts that develop in the abdominal cavity.A unique intra-abdominal ectopic bronchogenic cyst with a mucinous neoplasm that was producing carcinoembryonic antigen(CEA),harboring a GNAS mutation,is reported.The present case may contribute to clarifying the mechanism of tumorigenesis and malignant transformation of ectopic bronchogenic cysts.CASE SUMMARY In 2007,a man in his 50s was incidentally found to have an intra-abdominal cystic mass,8 cm in diameter.Surgical resection was recommended,but he preferred to remain under observation.In 2020,his serum CEA level increased to 26.7 ng/mL,and abdominal computed tomography showed a 15 cm×12 cm,multifocal,cystic mass located predominantly on the lesser curvature of the stomach.Since malignancy could not be ruled out,he finally underwent surgical resection.Histologically,the cystic wall was lined by ciliated columnar epithelium,accompanied by bronchial gland-like tissue,bronchial cartilage,and smooth muscle.Part of the cyst consisted of atypical columnar epithelium with an MIB-1 index of 5%and positive for CEA.Moreover,a GNAS mutation(p.R201C)was detected in the atypical epithelium,leading to a diagnosis of an ectopic bronchogenic cyst with a low-grade mucinous neoplasm.The patient is currently undergoing outpatient follow-up without recurrence.CONCLUSION An extremely rare case of an abdominal bronchogenic cyst with a low-grade mucinous neoplasm harboring a GNAS mutation was reported.

Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei

Pseudomyxoma peritonei(PMP) is an indolent malignant syndrome. The standard treatment for PMP is cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy(CRS + HIPEC). However, the high recurrence rate and latent clinical symptoms and signs are major obstacles to further improving clinical outcomes. Moreover, patients in advanced stages receive little benefit from CRS + HIPEC due to widespread intraperitoneal metastases. Another challenge in PMP treatment involves the progressive sclerosis of PMP cell-secreted mucus, which is often increased due to activating mutations in the gene coding for guanine nucleotide-binding protein alpha subunit(GNAS). Consequently, the development of other PMP therapies is urgently needed. Several immune-related therapies have shown promise, including the use of bacterium-derived non-specific immunogenic agents, radioimmunotherapeutic agents, and tumor cell-derived neoantigens, but a well-recognized immunotherapy has not been established. In this review the roles of GNAS mutations in the promotion of mucin secretion and disease development are discussed. In addition, the immunologic features of the PMP microenvironment and immune-associated treatments are discussed to summarize the current understanding of key features of the disease and to facilitate the development of immunotherapies.