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Systematic Investigation of Expression of G2/M Transition Genes Reveals CDC25 Alteration in Nonfunctioning Pituitary Adenomas

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Pathology & Oncology Research

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.

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Acknowledgements

This work has been funded by National Development Agency (KTIA_AIK-2-2012-0010 to Karoly Racz) and by Hungarian Scientific Research Grant (OTKA PD116093 to Henriett Butz). Attila Patocs received the „Lendulet” grant from Hungarian Academy of Sciences.

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Authors and Affiliations

  1. Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, 46 Szentkirályi str, Budapest, H-1088, Hungary

    Henriett Butz & Károly Rácz

  2. 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary

    Kinga Németh, Dóra Czenke, Péter Igaz, Károly Rácz & Attila Patócs

  3. MTA-SE „Lendulet” Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

    István Likó & Attila Patócs

  4. National Institute of Neurosurgery, Budapest, Hungary

    Sándor Czirják

  5. Institute of Forensic Medicine, University of Belgrade - School of Medicine, Belgrade, Serbia

    Vladimir Zivkovic

  6. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    Kornélia Baghy & Ilona Kovalszky

  7. Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK

    Márta Korbonits

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  1. Henriett Butz
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Electronic supplementary material

Supplementary Fig. 1.

(A) Expression of anterior pituitary hormones’ transcripts and POU1F1 transcription factor. (B) Endogenous controls in normal (NP) and nonfunctioning pituitary adenoma (NFPA) tissues. (GIF 35 kb)

High resolution image (TIFF 2.98 mb)

Supplementary Fig. 2.

Correlations among the G2/M mRNA expression levels. Red indicates positive, green indicates negative correlations (in all cases p<0.05). Black represents no correlation. (GIF 54 kb)

High resolution image (TIFF 4.02 mb)

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Butz, H., Németh, K., Czenke, D. et al. Systematic Investigation of Expression of G2/M Transition Genes Reveals CDC25 Alteration in Nonfunctioning Pituitary Adenomas. Pathol. Oncol. Res. 23, 633–641 (2017). https://doi.org/10.1007/s12253-016-0163-5

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