MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas

Stilling, Gail A.; Sun, Zhifu; Zhang, Shuya; Jin, Long; Righi, Alberto; Kovaćs, Gábor L.; Korbonits, Márta; Scheithauer, Bernd W.; Kovács, Kálmán; Lloyd, Ricardo V.

doi:10.1007/s12020-010-9346-0

Cited by 80 publications

(54 citation statements)

References 36 publications

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“…[35][36][37] The possible involvement of miRNAs in human pituitary tumors has also been reported. Stilling et al 38 profiled miRNA expression using a microarray technique and found that 188 miRNAs are up-regulated and 160 miRNAs are down-regulated in corticotroph adenomas, compared with normal pituitaries. Bottoni et al 39 reported that expression of miR-15a and of miR-16-1 is significantly reduced in both corticotroph adenomas and prolactinomas.…”

Section: Discussionmentioning

confidence: 99%

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

Cheunsuchon

Zhou

Zhang

et al. 2011

The American Journal of Pathology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Cheunsuchon

Zhou

Zhang

et al. 2011

The American Journal of Pathology

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“…It should be noted that Stilling et al 81 found that miR-493 was significantly underexpressed in functional ACTHPAs compared to that in the normal pituitary gland. miR-493 is a known tumor-suppressor miRNA.…”

Section: Mirna Expressionmentioning

confidence: 94%

Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

Seltzer¹,

Ashton²,

Scotton³

et al. 2015

FOC

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OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27Kip1, CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.

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“…Kimutatták továbbá, hogy a miR-141-et gyengén expresszáló ACTH-termelő adenomák esetében nagyobb a sebészeti eltávolítás utáni gyógyulás aránya [40]. Egy másik munkacsoport szintén ACTH-termelő agyalapimirigy-daganatok vizsgálata során kimutatta, hogy a miR-122 és a miR-493 erősebben fejeződik ki carcinomában, mint adenomában és normálszövetben, ami arra utal, hogy ezeknek a miRNS-eknek szerepük lehet a malignitás kialakulásában is [41].…”

Section: Mirns-expressziós Eltérések Az Agyalapimirigy-daganatokbanunclassified

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

et al. 2018

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A mikro-RNS-ek rövid, egyszálú RNS-molekulák, melyek szabályozó szerepüket más gének poszttranszkripcionális módosítása révén fejtik ki. A humán fehérjéket kódoló gének nagyjából 30%-a miRNS-ek szabályozása alatt is áll, aminek révén olyan alapvető folyamatokat befolyásolnak, mint a sejtosztódás, -differenciálódás és sejthalál. Számos daganattípussal kapcsolatban írták már le a megváltozott miRNS-expressziós mintázatot, és egyre több közlemény veti fel, hogy a miRNS-ek, mint terápiás célpontok is szóba jöhetnek. A csökkent expressziójú miRNS-ek adásán, illetve az emelkedett expressziót mutató miRNS-ek gátlásán keresztül nem csak egyetlen gén, hanem egész jelátviteli útvonalak befolyásolása is lehetővé válhat. Az agyalapimirigy-daganatok a leggyakoribb intracranialis tumorok közé tartoznak. Gyakoriságuk ellenére a sporadikusan előforduló adenomák kialakulásának molekuláris mechanizmusa még kevéssé van feltárva. Az utóbbi években egyre több bizonyíték utal arra, hogy a mikro-RNS-eknek fontos szerepük van az adenomagenezisben. Összefoglalónkban az agyalapimirigy-adenomákban leírt miRNS-ek szerepét kíván-juk bemutatni, valamint felvázolni a miRNS-ekhez kapcsolódó terápiás lehetőségeket. Orv Hetil. 2018; 159(7): 252-259. Kulcsszavak: mikro-RNS, agyalapimirigy-adenoma, biomarkerThe role of miRNAs in the pathogenesis of pituitary adenomas MicroRNAs (miRNAs) are short, single stranded RNA molecules which play regulatory roles through posttranscriptional regulation of their target genes. Based on our current knowledge, more than 30% of the human protein-coding genes are regulated by miRNAs, hence influencing basic cellular mechanisms including cell proliferation, differentiation and cell death. Differential miRNA expression pattern has been detected in many different types of tumors and, recently, several publications have referred to miRNAs as potential therapeutic targets. Through adjustment of miRNA levels by artificial miRNAs administration or miRNA inhibition, we can influence not only one target gene but also complex biological pathways. Pituitary adenoma is the second most frequent intracranial tumor. In spite of this, the molecular mechanism of the pituitary adenoma formation is not yet entirely revealed. Recently, more and more evidences have been found suggesting that miRNAs have an important role in pituitary adenoma pathogenesis. Here, we summarize the recent results related to this role and highlight the therapeutic potentials in pituitary adenomas.

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MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas

Cited by 80 publications

References 36 publications

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

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

Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

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

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