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

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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.

ABBREVIATIONS cDNA = complementary DNA; CNFPA = clinical nonfunctioning PA; Dox = doxycycline; FBS = fetal bovine serum; FITC = fluorescein isothiocyanate; HRP = horseradish peroxidase; lncRNA = long ncRNA; miRNA = microRNA; NC = negative control; ncRNA = noncoding RNA; NP = normal pituitary; PA = pituitary adenoma; PBS = phosphate-buffered saline; PDFS = pituitary-derived folliculostellate; PI = propidium iodide; PVDF = polyvinylidene fluoride; qRT-PCR = quantitative real-time polymerase chain reaction; TRITC = trimethylrhodamine isothiocyanate.

Supplementary Materials

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Article Information

Contributor Notes

Correspondence Haijun Wang: The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. wanghaij@mail.sysu.edu.cn.INCLUDE WHEN CITING Published online January 3, 2020; DOI: 10.3171/2019.10.JNS191959.

D.Z. and Z.X. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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