Association between Intracellular Calcium Signaling and Tumor Recurrence in Human Non-Functioning Pituitary Adenomas.

Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.

MEG3/MIR-376B-3P/HMGA2 axis is involved in pituitary tumor invasiveness.

OBJECTIVE: To date, long noncoding RNAs (lncRNAs) have proven to function as key regulators in tumorigenesis. Among these lncRNAs, MEG3 displays low levels in various neoplasms and tumor cell lines. However, the regulatory mechanism of MEG3 and MIR-376B-3P, one of the microRNAs from downstream gene clusters of the DLK1-MEG3 locus, remains insufficiently defined. METHODS: The authors used quantitative real-time polymerase chain reaction analysis to analyze whether decreased MEG3 and MIR-376B-3P expression levels were associated with the invasiveness of clinical nonfunctioning pituitary adenomas (CNFPAs) in 30 patients. Furthermore, functional experiments unveiled the pathophysiological role of MEG3, MIR-376B-3P, and HMGA2 in pituitary-derived folliculostellate (PDFS) cell lines. Moreover, dual-luciferase reporter assay, Western blot analysis, and immunofluorescence were applied to reveal the correlations among MEG3, MIR-376B-3P, and HMGA2. RESULTS: MEG3 and MIR-376B-3P were decreased in patients with CNFPA, and their transcriptional levels were highly associated with invasive CNFPAs. Moreover, excessive expression of MEG3 and MIR-376B-3P inhibited tumorigenesis and promoted apoptosis in PDFS cells. Importantly, the authors found that MEG3 acted as an enhancer of MIR-376B-3P expression. Furthermore, as a target gene of MIR-376B-3P, HMGA2 served as an oncogene in pituitary adenoma and could be negatively regulated by MEG3 via enriching MIR-376B-3P. CONCLUSIONS: This study offers a novel mechanism of an MEG3/MIR-376B-3P/HMGA2 regulatory network in CNFPAs, which may become a breakthrough for anticancer treatments.