Differential expression of microRNAs in GH-secreting pituitary adenomas

Abstract

BackgroundThe purpose of this study was to (1) identify specific miRNAs in growth hormones (GH)-secreting pituitary adenomas; (2) determine the relationship between the expression of these miRNAs and tumor size, somatostatin analogs treatment, and responsiveness to somatostatin analogs (SSA).MethodsFifteen GH-secreting adenomas patients were treated with lanreotide for 4 months before surgery. Patients with 50% reduction of GH secretion by lanreotide were considered as SSA responders, while patients with less than 50% of GH reduction were considered as SSA nonresponders. We analyzed the miRNAs in 21 GH-secreting pituitary adenomas and 6 normal pituitaries by miRCURY™ LNA array and some differentially expressed miRNAs were validated by quantitative real-time PCR.ResultsFifty-two miRNAs were differentially expressed between GH-secreting pituitary adenomas and normal pituitaries. Differential expression of 9 miRNAs was observed between micro- and macro-adenomas. Thirteen miRNAs were differentially expressed between tumor samples from lanreotide-treated patients and those from lanreotide-untreated patients. Seven miRNAs were differentially expressed between SSA responders or GH nonresponders. Several identified miRNAs may be involved in cell proliferation, apoptosis, cancer development and progression.ConclusionsOur results indicate that altered miRNAs expression is involved in GH-secreting pituitary adenomas transformation, which will shed light on the mechanisms for the treatment of acromegaly by SSA. Identification and characterization of the targets of altered miRNAs genes may elucidate molecular mechanisms involved in the pathogenesis of pituitary adenoma.

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

“…However, although technical limitations precluded us from determining the relative or absolute contribution of each of these pathways, our conclusions are reinforced by the independent approaches that reach similar conclusions and described above. [11,14,45] Thus far, investigations characterizing the inappropriate expression of miRNA in the genesis of pituitary adenomas has already led to the identification of subtype-specific miRNA profiles [46,47,16], identification of miRNA that show correlations with tumour size [40] or are predictive of tumor sensitivity and or response to therapeutic interventions. [47,16] and have been subject to recent and extensive review, [48][49][50][51].…”

A mikro-RNS-ek szerepe az agyalapimirigy-daganatok tumorbiológiájában

“…Ezek kö-zül 6 miRNS (miR-450b-5p, miR-424, miR-503, miR-542-3p, miR-629, miR-214) expressziója csökkent, míg egy miRNS-é (miR-592) nőtt a daganatokban a normál-szövethez képest. Hasonló megállapítást tettek Mao és mtsai, akik GH-termelő adenomákban 52 eltérően expresszálódó miRNS-t azonosítottak a normálszövethez képest, melyek közül 9 (miR-184, miR-524-5p, miR-629, miR-766, miR-124, miR-222, miR-32, miR-744, miR-765) alkalmas lehet a macroadenomák microadenomáktól való elkülönítésére [43].…”

“…Sőt azonosítottak 7 miRNS-t, melyek különböztek (miR-125b, miR-886-5p emelkedett, miR-125a-5p, miR-198, miR-503, miR-524-5p és miR-630 csökkent) a szomatosztatinanalóg-kezelésre reagáló vs. nonreszponder betegek daganatszöveteiben [43]. Figyelembe véve, hogy az azonosított miRNS-ek közül többnek szerepe van a sejtproliferációban, az apoptózis-ban és a tumorképződésben, a szerzők feltételezik, hogy az eltérően kifejeződő miRNS-ek szerepet játszhatnak a GH-termelő adenomák transzformációjában, és felhívják a figyelmet arra, hogy ezek targetjeinek vizsgálata segít-het a patogenezis pontosabb megértésében [43]. Emellett, ha ezeknek a vizsgálatoknak az eredményeit megerősítik nagyobb esetszámon és hosszabb kezelésen áteső betegeken, akkor a miRNS-mintázat alapján akár megbecsülhető lehet, hogy egy beteg reagálni fog-e a szomatosztatinanalóg-kezelésre [73].…”

The Genetics of Pituitary Adenomas

“…In GH-secreting adenomas 52 miRNAs have been reported to be differentially expressed (23 up-regulated and 29 down-regulated). Nine of them are differentially expressed between micro-and macro-adenomas (Mao et al, 2010). Also in NFPAs, six miRNA, including miR-140, miR-99b, miR-99a, miR-30c, miR-30b and miR-138-2, (the first five up-regulated and the last one down-regulated) are differentially expressed in macro-versus micro-adenomas (Bottoni et al, 2007).…”

“…In PA of different histotypes, a significant down-regulation of miR-15a and miR-16-1, that inversely correlates with tumour diameter and directly correlates with the secretion of the anti-neoplastic cytokine p43, has been shown in comparison with normal pituitary (Bottoni et al, 2005). The analysis of the differential expression profile of PA of specific histotypes in comparison with normal pituitary, has identified several other miRNAs potentially involved in pituitary tumorigenesis (Bottoni et al, 2007;Amaral et al, 2009;Mao et al, 2010). In ACTH-secreting adenomas six more miRNAs (miR-145, miR-21, miR-141, let-7a, miR-150 and miR-143), other than miR-15a and miR-16, have been shown to be down-regulated (Amaral et al, 2009).…”