C/D-box snoRNA-derived RNA production is associated with malignant transformation and metastatic progression in prostate cancer
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Elena S. Martens-Uzunova1, Youri Hoogstrate1, Anton Kalsbeek1, Bas Pigmans1, Mirella Vredenbregt-van den Berg1, Natasja Dits1, Søren Jensby Nielsen2,3, Adam Baker2,4, Tapio Visakorpi5, Chris Bangma1 and Guido Jenster1
1 Department of Urology, Erasmus MC, Rotterdam, The Netherlands
2 Exiqon A/S, Vedbaek, Denmark
3 Nuevolution A/S, Copenhagen, Denmark
4 Chr. Hansen A/S, Hørsholm, Denmark
5 Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland
Elena S. Martens-Uzunova, email:
Keywords: snoRNA, sdRNA, SNORD78, GAS5, prostate cancer
Received: February 05, 2015 Accepted: May 02, 2015 Published: May 19, 2015
Small nucleolar RNAs (snoRNAs) are dynamically regulated in different tissues and affected in disease. SnoRNAs are processed further to stable smaller RNAs. We sequenced the small RNA transcriptome of prostate cancer (PCa) at different PCa stages and generated a quantified catalogue of 3927 small non-coding RNAs (sncRNAs) detected in normal and malignant prostate tissue. From these, only 1524 are microRNAs. The remaining 2401 sncRNAs represent stable sncRNAs species that originate from snoRNA, tRNA and other sncRNAs. We show that snoRNA-derived RNAs (sdRNAs) display stronger differential expression than microRNAs and are massively upregulated in PCa. SdRNAs account for at least one third of all small RNAs with expression changes in tumor compared to normal adjacent tissue. Multiple sdRNAs can be produced from one snoRNA in a manner related to the conservation of structural snoRNA motifs. Q-PCR analysis in an independent patient cohort (n=106) confirmed the processing patterns of selected snoRNAs (SNORD44, SNORD78, SNORD74 and SNORD81) and the cancer-associated up-regulation of their sdRNAs observed in sequencing data. Importantly, expression of SNORD78 and its sdRNA is significantly higher in a subset of patients that developed metastatic disease demonstrating that snoRNA and sdRNAs may present as novel diagnostic and/or prognostic biomarkers for PCa.
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