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MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas

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Abstract

MicroRNAs (miRs) are small, 16–29 nucleotide long, non-coding RNA molecules which regulate the stability or translational efficiency of targeted mRNAs via RNA interference. MiRs participate in the control of cell proliferation, cell differentiation, signal transduction, cell death, and they play a role in carcinogenesis. The aims of our study were to analyse the expression profile of miRs in sporadic clinically non-functioning pituitary adenomas (NFPA) and in normal pituitary tissues, and to identify biological pathways altered in these pituitary tumors. MiR expression profiles of 12 pituitary tissue specimens (8 NFPA and 4 normal pituitary tissues) were determined using miR array based on quantitative real-time PCR with 678 different primers. Five overexpressed miRs and mRNA expression of Smads (Smad1-9), MEG and DLK1 genes were evaluated with individual Taqman assays in 10 NFPA and 10 normal pituitary tissues. Pathway analysis was performed by the DIANA-mirPath tool. Complex bioinformatical analysis by multiple algorithms and association studies between miRs, Smad3 and tumor size was performed. Of the 457 miRs expressed in both NFPA and normal tissues, 162 were significantly under- or overexpressed in NFPA compared to normal pituitary tissues Expression of Smad3, Smad6, Smad9, MEG and DLK1 was significantly lower in NFPA than in normal tissues. Pathway analysis together with in silico target prediction analysis indicated possible downregulation of the TGFβ signaling pathway in NFPA by a specific subset of miRs. Five miRs predicted to target Smad3 (miR-135a, miR-140-5p, miR-582-3p, miR-582-5p and miR-938) were overexpressed. Correlation was observed between the expression of seven overexpressed miRs and tumor size. Downregulation of the TGFβ signaling through Smad3 via miRs may have a possible role in the complex regulation of signaling pathways involved in the tumorigenesis process of NFPA.

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Acknowledgments

We are very grateful to Dr V. Zivkovic, Belgrade, Serbia for the provision of the control samples. This work was supported by grant ETT 040-09. A.P. is a recipient of János Bólyai Research Fellowship.

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Authors and Affiliations

  1. 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, 46 Szentkirályi str., Budapest, 1088, Hungary

    Henriett Butz, Péter Igaz, Károly Rácz & Attila Patócs

  2. Gedeon Richter Plc, Budapest, Hungary

    István Likó

  3. National Institute of Neurosurgery, Budapest, Hungary

    Sándor Czirják

  4. Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK

    Márta Korbonits

  5. Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary

    Attila Patócs

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  1. Henriett Butz
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Butz, H., Likó, I., Czirják, S. et al. MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas. Pituitary 14, 112–124 (2011). https://doi.org/10.1007/s11102-010-0268-x

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