Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway.

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.

Glaucoma de ángulo abierto secundario a cortisona endógena por microadenoma hipofisario en un paciente joven, a propósito de un caso / Open angle glaucoma secondary to endogenous cortisone due to pituitary microadenoma in a young patient, a case report

CASO CLÍNICO: Varón de 31 años que fue derivado para valoración tras ser diagnosticado de síndrome de Cushing secundario a un microadenoma hipofisario. En la exploración se observó reducción de la agudeza visual y presión intraocular (PIO) de 48 mmHg en ambos ojos. El segmento anterior fue normal, la papila excavada y el ángulo abierto explorado mediante gonioscopia. Se realizó también campimetría que reveló una afectación avanzada. Se diagnosticó de glaucoma secundario a corticosteroides endógenos y se inició tratamiento médico a la espera de la extirpación del adenoma. La PIO no se normalizó tras la extirpación incompleta del adenoma, por lo que se optó por realizar trabeculectomía para controlarla. Como conclusiones: ante una hipertensión ocular con tumor hipofisario se debe sospechar glaucoma secundario a cortisona endógena; el tratamiento precoz del tumor es necesario para normalizar los niveles de la cortisona y controlar la PIO, el diagnóstico tardío o el tratamiento incompleto de estos tumores puede llevar a no obtener un control adecuado de la PIO

CASE REPORT: A 31-year-old male was referred for evaluation after being diagnosed with Cushing syndrome secondary to a pituitary microadenoma. He presented with a reduced visual acuity and high intraocular pressure (IOP) of 48mmHg in both eyes. The examination with biomicroscopy showed normal anterior segment, increased cup to disc ratio, and open angle. There was a moderate-advanced involvement in the visual field. The patient was diagnosed with glaucoma secondary to endogenous corticosteroids, and medical treatment was initiated pending the removal of the adenoma. The IOP did not return to normal after the incomplete removal of the adenoma, so a trabeculectomy was performed to control the IOP. As conclusions: In the case of an ocular hypertension with pituitary tumour, secondary glaucoma to endogenous cortisone should be suspected. Early treatment of the tumour is necessary to bring the cortisone and IOP levels back to normal. Late diagnosis or incomplete treatment of these tumours may lead to not obtaining adequate IOP control