title: Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas.
abstract: 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.
authors.affiliation: Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114, USA.
authors.forename: Pornsuk
authors.initials: P
authors.lastname: Cheunsuchon
authors.forename: Yunli
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xun
authors.initials: X
authors.lastname: Zhang
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.forename: Wendy
authors.initials: W
authors.lastname: Chen
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Rice
authors.forename: E
authors.initials: E
authors.lastname: Tessa Hedley-Whyte
authors.forename: Brooke
authors.initials: B
authors.lastname: Swearingen
authors.forename: Anne
authors.initials: A
authors.lastname: Klibanski
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D005220:Fathers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056426:Genetic Loci / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009035:Mothers; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011506:Proteins; D062085:RNA, Long Noncoding