Endocrine Abstracts (2012) 29 OC4.6

Cell cycle G2/M transition is modulated by microRNAs in pituitary adenomas

H. Butz1, I. Likó2, S. Czirják3, M. Korbonits4, K. Rácz1 & A. Patócs1,5

1Faculty of Medicine, Semmelweis University, Budapest, Hungary; 2Gedeon Richter Plc, Budapest, Hungary; 3National Institute of Neurosurgery, Budapest, Hungary; 4Barts and the London School of Medicine, Queen Mary University of London, London, UK; 5Hungarian Academy of Sciences, Budapest, Hungary.

Background: Although pituitary adenomas are common endocrine neoplasms, the background of their pathogenesis has not clearly revealed. G1/S checkpoint alterations of the cell cycle have already been described in these tumours. MicroRNAs (miRs) which are small, non-coding RNA molecules, and posttranscriptionally regulate protein expression have also identified as potential pathogenic factors in certain cases. Our aim was to determine miR expression profile in pituitary adenomas, and validate targets of miRs that differentially expressed between normal and adenomatous pituitary.

Materials and methods: 57 pituitary tissue samples were analyzed. MiR expression profiles were determined by TaqMan Low Density Arrays, selected miRs and genes were validated by real-time PCR. Multiple in silico target prediction algorithms were applied for identification of miR–mRNA interactions. Protein changes were detected using immunhistochemistry and Western blot. mRNA–miR interactions were proved using in vitro luciferase reporter system.

Results: 162 differentially expressed miRs and those which were correlated with tumour size were determined in pituitary adenomas compared to normal tissues. Using target prediction we identified the downregulation of the Wee1 kinase protein by three overexpressed miRs targeting Wee1 proved by luciferase reporter gene experiment. 6 of 24 genes involved in G2/M transition were differentially expressed in adenoma tissues compared to normal tissue. Among CDC25 family that has opposite function to Wee1 Cdc25A and CDC25C were found to be overexpressed and its targeting miRs were underxpressed in pituitary adenomas.

Conclusion: Wee1 and CDC25 have opposite regulator effect on Cyclin B–CDK1 complex that controls G2/M transition of cell cycle. Our results show that in pituitary adenomas G2/M transition is complexly regulated by RNA interference through Wee1 and CDC25. Therapeutical approaches targeting miRs and members of G2/M transition are under development and based on our results these may have therapeutical significance in treatment of pituitary adenomas.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.

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