The two most common histological subtypes of malignant germ cell tumour are distinguished by global microRNA profiles, associated with differential transcription factor expression
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  • 作者:Matthew J Murray (1)
    Harpreet K Saini (2)
    Stijn van Dongen (2)
    Roger D Palmer (1)
    Balaji Muralidhar (1)
    Mark R Pett (1)
    Matias Piipari (3)
    Claire M Thornton (4)
    James C Nicholson (5)
    Anton J Enright (2)
    Nicholas Coleman (1) (6)
  • 刊名:Molecular Cancer
  • 出版年:2010
  • 出版时间:December 2010
  • 年:2010
  • 卷:9
  • 期:1
  • 全文大小:1841KB
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  • 作者单位:Matthew J Murray (1)
    Harpreet K Saini (2)
    Stijn van Dongen (2)
    Roger D Palmer (1)
    Balaji Muralidhar (1)
    Mark R Pett (1)
    Matias Piipari (3)
    Claire M Thornton (4)
    James C Nicholson (5)
    Anton J Enright (2)
    Nicholas Coleman (1) (6)

    1. Medical Research Council Cancer Cell Unit, Cambridge, CB2 0XZ, UK
    2. EMBL-European Bioinformatics Institute, CB10 1SD, Hinxton, Cambridge, UK
    3. Wellcome Trust Sanger Institute, CB10 1SA, Hinxton, Cambridge, UK
    4. Department of Pathology, Royal Group of Hospitals Trust, Belfast, UK
    5. Department of Paediatric Haematology and Oncology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
    6. Department of Pathology, University of Cambridge, CB2 1QP, UK
  • ISSN:1476-4598
文摘
Background We hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas. Results By direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs. Conclusions Differential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.

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