Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma.
Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma.
复制标题
DOI：
10.1186/s12885-017-3711-9
复制
发表时间：
2017-11-13
期刊：
影响因子：
3.8
通讯作者：
Bailey JA
中科院分区：
文献类型：
--
作者：
Oduor CI;Kaymaz Y;Chelimo K;Otieno JA;Ong'echa JM;Moormann AM;Bailey JA
伯基特淋巴瘤（BL）的特征在于c-myc癌基因的过度表达，这在绝大多数情况下是IGH/MYC易位的结果。虽然myc是种子事件，但BL是遗传和表观遗传变化的复杂混合物，导致编码和非编码转录物的失调。新出现的证据表明，mRNA转录通过miRNA的异常调节可能是淋巴瘤发生的一个重要因素。然而，相对于正常生发中心（GC）B细胞，这些miRNA的改变及其与其假定mRNA靶点的相关性尚未得到广泛研究。使用更灵敏和特异的转录组深度测序，我们比较了先前发表的一组GC B细胞和eBL肿瘤的小miRNA和长mRNA。MiRWalk2.0用于鉴定去调控的miRNAs的经验证的靶基因，这对于理解与eBL发育相关的调控网络将是重要的。我们发现了211个差异表达（DE）基因（79个上调和132个下调）和49个DE miRNA（22个上调和27个下调）。基因集富集分析鉴定了一组MYC调控基因的富集。基于网络传播的方法和相关的miRNA-mRNA表达分析鉴定了失调的miRNAs，包括miR-17~95簇成员及其靶基因，它们具有不同的致癌特性，对eBL淋巴瘤的发生至关重要。所有这些发现的核心是，我们观察到ATM和NLK基因的下调，这两个基因代表了eBL肿瘤细胞中响应DNA损伤的重要调节因子。这些肿瘤抑制因子被多种上调的miRNA（miR-19 b-3 p、miR-26 a-5 p、miR-30 b-5 p、miR-92 a-5 p和miR-27 b-3 p）靶向，这可以解释它们在eBL中的异常表达。由于miRNA介导的ATM和NLK的调节以及TFAP 4的上调导致的p53诱导和功能的组合丧失可能是人miRNA在eBL肿瘤发生中的中心作用。这有利于IGH/MYC染色体易位的eBL肿瘤细胞的存活，并促进MYC诱导的细胞周期进展，启动eBL淋巴瘤发生。eBL中相对于GC B细胞的miRNA-mRNA相互作用的这种表征提供了eBL中miRNA介导的转录调控的新见解，这对于新的改进的治疗策略是潜在有用的。本文的在线版本（10.1186/s12885-017-3711-9）包含补充材料，可供授权用户使用。
Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies. The online version of this article (10.1186/s12885-017-3711-9) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
2.9
作者：
Hafsi S;Candido S;Maestro R;Falzone L;Soua Z;Bonavida B;Spandidos DA;Libra M
通讯作者：
Libra M
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
4.4
作者：
Bovolenta LA;Acencio ML;Lemke N
通讯作者：
Lemke N
影响因子：
158.5
作者：
Dave, Sandeep S.;Fu, Kai;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
9.6
作者：
BURKITT, D
通讯作者：
BURKITT, D