Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas.

DLK1-MEG3 is 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 down-regulated, 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.

Cheunsuchon P ，Zhou Y ，Zhang X ，Lee H ，Chen W ，Nakayama Y ，Rice KA ，Tessa Hedley-Whyte E ，Swearingen B ，Klibanski A ... -  《-》

Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas.

Gejman R ，Batista DL ，Zhong Y ，Zhou Y ，Zhang X ，Swearingen B ，Stratakis CA ，Hedley-Whyte ET ，Klibanski A ... -  《-》

Functional characterization of DLK1/MEG3 locus on chromosome 14q32.2 reveals the differentiation of pituitary neuroendocrine tumors.

Chen Y ，Gao H ，Liu Q ，Xie W ，Li B ，Cheng S ，Guo J ，Fang Q ，Zhu H ，Wang Z ，Wang J ，Li C ，Zhang Y ... -  《Aging-US》

Analysis of the Paternally-Imprinted DLK1-MEG3 and IGF2-H19 Tandem Gene Loci in NT2 Embryonal Carcinoma Cells Identifies DLK1 as a Potential Therapeutic Target.

Sellers ZP ，Schneider G ，Maj M ，Ratajczak MZ ... -  《-》

CXCL12-regulated miR-370-3p functions as a tumor suppressor gene by targeting HMGA2 in nonfunctional pituitary adenomas.

Silencing of noncoding genes within the imprinted DLK1-MEG3 locus is exclusive to human nonfunctional pituitary adenomas (NFPAs), but the exact mechanism is still unclear. This study was designed to demonstrate the impact of CXCL12 on the expression of miRNAs within this locus and phenotypic alterations of NFPAs. Human NFPA samples were collected for screening differentially expressed miRNAs by CXCL12. Target mRNAs of the miRNAs were predicted and verified in vitro. Tumor phenotypic alterations were also tested. Another 51 NFPA samples were enrolled to examine the correlation and clinical features. The expression of miR-370 was decreased by CXCL12 treatment in NFPAs. miR-370-3p was predicted and verified to target HMGA2 as a tumor suppressor gene. Overexpression of HMGA2 inhibited its antitumor function. miR-370-3p was downregulated and HMGA2 was upregulated significantly in High grade NFPAs. In conclusion, the CXCL12/miR-370-3p/HMGA2 signaling pathway is involved in tumor growth and invasiveness of NFPAs.

Cai F ，Dai C ，Chen S ，Wu Q ，Liu X ，Hong Y ，Wang Z ，Li L ，Yan W ，Wang R ，Zhang J ... -  《-》