Epigenetic silencing of genes and microRNAs within the imprinted Dlk1-Dio3 region at human chromosome 14.32 in giant cell tumor of bone

BMC Cancer

Burkhard Lehner¹  Pierre Kunz¹  Heiner Saehr¹  Joerg Fellenberg¹ 

[1] Research Centre for Experimental Orthopedics, Department of Orthopedics, Trauma Surgery and Paraplegia, Orthopedic University Hospital Heidelberg, Schlierbacher Landstr 200a, Heidelberg 69118, Germany

关键词: Methylation;    Epigenetics;    MicroRNA;    Mesenchymal stem cell;    Giant cell tumor;   

Others  :  855181
DOI  :  10.1186/1471-2407-14-495

 received in 2014-03-18, accepted in 2014-07-04,  发布年份 2014

【 摘 要 】

Background

Growing evidence exists that the neoplastic stromal cell population (GCTSC) within giant cell tumors (GCT) originates from mesenchymal stem cells (MSC). In a previous study we identified a microRNA signature that differentiates between these cell types. Five differentially expressed microRNAs are located within the Dlk1-Dio3 region on chromosome 14. Aberrant regulation within this region is known to influence cell growth, differentiation and the development of cancer. The aim of this study was to elucidate the involvement of deregulations within the Dlk1-Dio3 region in GCT pathogenesis.

Methods

Quantitative gene and microRNA expression analyses were performed on GCTSCs and MSCs with or without treatment with epigenetic modifiers. Methylation analysis of differentially methylated regions was performed by bisulfite sequencing.

Results

In addition to microRNA silencing we detected a significant downregulation of Dlk1, Meg3 and Meg8 in GCTSCs compared to MSCs. DNA methylation analyses of the Meg3-DMR and IG-DMR revealed a frequent hypermethylation within the IG-DMR in GCTs. Epigenetic modification could restore expression of some but not all analyzed genes and microRNAs suggesting further regulatory mechanisms.

Conclusion

Epigenetic silencing of genes and microRNAs within the Dlk1-Dio3 region is a common event in GCTSCs, in part mediated by hypermethylation within the IG-DMR. The identified genes, micro RNAs and microRNA target genes might be valuable targets for the development of improved strategies for GCT diagnosis and therapy.

【 授权许可】

   
2014 Lehner et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

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