title: Systematic Investigation of Expression of G2/M Transition Genes Reveals CDC25 Alteration in Nonfunctioning Pituitary Adenomas.
abstract: Dysregulation of G1/S checkpoint of cell cycle has been reported in pituitary adenomas. In addition, our previous finding showing that deregulation of Wee1 kinase by microRNAs together with other studies demonstrating alteration of G2/M transition in nonfunctioning pituitary adenomas (NFPAs) suggest that G2/M transition may also be important in pituitary tumorigenesis. To systematically study the expression of members of the G2/M transition in NFPAs and to investigate potential microRNA (miRNA) involvement. Totally, 80 NFPA and 14 normal pituitary (NP) tissues were examined. Expression of 46 genes encoding members of the G2/M transition was profiled on 34 NFPA and 10 NP samples on TaqMan Low Density Array. Expression of CDC25A and two miRNAs targeting CDC25A were validated by individual quantitative real time PCR using TaqMan assays. Protein expression of CDC25A, CDC25C, CDK1 and phospho-CDK1 (Tyr-15) was investigated on tissue microarray and immunohistochemistry. Several genes' expression alteration were observed in NFPA compared to normal tissues by transcription profiling. On protein level CDC25A and both the total and the phospho-CDK1 were overexpressed in adenoma tissues. CDC25A correlated with nuclear localized CDK1 (nCDK1) and with tumor size and nCDK1 with Ki-67 index. Comparing primary vs. recurrent adenomas we found that Ki-67 proliferation index was higher and phospho-CDK1 (inactive form) was downregulated in recurrent tumors compared to primary adenomas. Investigating the potential causes behind CDC25A overexpression we could not find copy number variation at the coding region nor expression alteration of CDC25A regulating transcription factors however CDC25A targeting miRNAs were downregulated in NFPA and negatively correlated with CDC25A expression. Our results suggest that among alterations of G2/M transition of the cell cycle, overexpression of the CDK1 and CDC25A may have a role in the pathogenesis of the NFPA and that CDC25A is potentially regulated by miRNAs.
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, 46 Szentkirályi str, Budapest, H-1088, Hungary. butz.henriett@med.semmelweis-univ.hu.
authors.forename: Henriett
authors.initials: H
authors.lastname: Butz
authors.affiliation: 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Németh
authors.affiliation: 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Czenke
authors.affiliation: MTA-SE "Lendulet" Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Likó
authors.affiliation: National Institute of Neurosurgery, Budapest, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Czirják
authors.affiliation: Institute of Forensic Medicine, University of Belgrade - School of Medicine, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Zivkovic
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.affiliation: 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Igaz
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, 46 Szentkirályi str, Budapest, H-1088, Hungary.|2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Rácz
authors.affiliation: 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.|MTA-SE "Lendulet" Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
mesh_terms: D000236:Adenoma / Q000235:genetics*; D016203:CDC2 Protein Kinase / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics*; D020687:cdc25 Phosphatases / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D016203:CDC2 Protein Kinase; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
keywords: CDC25A; Cell cycle; G2/M transition; Pituitary adenoma; miRNA