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In AtT20 cells, dexamethasone (DEX) increased the expression of miR-375, which has a seed sequence for Ssrt2, supporting the hypothesis that excessive GC exposure can lead to epigenetic SSTR2 downregulation. The current study aims to evaluate miR-375 levels by reverse transcription quantitative polymerase chain reaction in sera from patients with CD, human corticotroph pituitary tumors, normal pituitaries, and AtT20\/D16 and GH3 cells, and miR-375 impact on SSTR2 expression in AtT20\/D16 and human corticotroph pituitary tumors. SSTR2 protein expression and localization were evaluated by WB and IF in AtT20\/D16 and human primary cultures. Proliferation assay and flow cytometry were assessed to investigate the impact of miR-375 regulation on OCT treatment in AtT20\/D16. miR-375 levels were higher in sera from patients with CD than in healthy subjects, and in human corticotroph pituitary tumors than in normal pituitaries. AtT20\/D16 and GH3 exhibited an inverse expression pattern, with SSTR2 mRNA at low levels and miR-375 at high levels in AtT20\/D16 and an opposite expression pattern in GH3. DEX treatment significantly reduced SSTR2 gene expression, while miR-375 inhibition significantly increased SSTR2 membranous protein expression in AtT20\/D16 and primary cultures. Receptor internalization appeared stronger when OCT was combined with miR-375 inhibitor. The decreased cell proliferation induced by OCT was potentiated by miR-375 inhibition, increasing cells in early and late apoptosis, by inducing PARP, Caspase3, and ERK1\/2 phosphorylation. In conclusion, SSTR2 protein expression can be epigenetically downregulated by GC-induced miR-375 expression, at least partially influencing OCT action in corticotroph pituitary tumors.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf107","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T13:16:49Z","timestamp":1749475009000},"source":"Crossref","is-referenced-by-count":5,"title":["miR-375 Regulation of SSTR2 Expression in Corticotroph Pituitary Cells: Somatostatin Receptor Ligands Effects"],"prefix":"10.1210","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4276-8600","authenticated-orcid":false,"given":"Claudia","family":"Pivonello","sequence":"first","affiliation":[{"name":"Dipartimento di Sanit\u00e0 Pubblica, Universit\u00e0 Degli Studi di Napoli \u201cFederico II\u201d , Naples 80131 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