Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

Abstract

DLK1-MEG3is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly downregulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.

Downregulation of miR-410 targeting the cyclin B1 gene plays a role in pituitary gonadotroph tumors

“…In agreement with our data, miR-410 was previously found downregulated in NFPAs (nonfunctioning pituitary adenomas) adenomas, within the DLK1-MEG3 locus, which contains one of the largest miRNA clusters in humans, and its expression has been correlated with MEG3 (maternally expressed gene 3), a maternally expressed noncoding RNA frequently lost in clinically NFPAs of gonadotroph origin. 24 Moreover, other previous studies have evidenced a tumor suppressor activity for this miRNA. Indeed, miR-410 has been found downregulated gliomas 19 and gastric carcinomas 25 where lower miRNA-410 expression levels significantly correlated with the presence of lymph-node metastasis.…”

Pituitary adenoma: a literature review

“…Nor ma lia me hi po fi zës au diny je jo eks pre si ja yra ið reikð ta, o ser gant ne funk cio nuo janèia HA, ji ið nyks ta ar ba la bai su ma þë ja [23,29,36]. At liktuo se ty ri muo se, ieð kant ðio reið ki nio prie þas ties, bu vo atmes tos de le ci jos ir ki tos mu ta ci jos, ta èiau ras tas pa di dë jaes dvie jø re gio nø, IG-DMR ir MEG3-DMR, me ti li ni mas [37].…”

MANAGEMENT OF ENDOCRINE DISEASE: Clinicopathological classification and molecular markers of pituitary tumours for personalized therapeutic strategies

“…They act as tumour suppressors or oncogenes, depending on the function of the targeted genes, and seem to be involved in the regulation of many steps of tumour progression. Results from studies comparing pituitary tumours to normal pituitary (95,96,97,98,99,100,101,102,103,104,105,106,107,108) suggest that miRNA deregulation may play a key role in pituitary tumourigenesis. Indeed, D'Angelo et al (101) identified a set of miRNAs, including miR-34b, miR-326, miR-432, miR-548c-3p, miR-570 and miR-603, that were drastically and consistently down-regulated in GH adenomas and demonstrated that these miRNAs target genes with critical roles in pituitary tumourigenesis, such as high-mobility group A1 (HMGA1), HMGA2 and E2F1.…”