地方性 Burkitt 淋巴瘤中 miRNA 和 mRNA 深度测序表达谱的综合分析。
Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma.
机构信息
Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya.
出版信息
BMC Cancer. 2017 Nov 13;17(1):761. doi: 10.1186/s12885-017-3711-9.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
伯基特淋巴瘤（BL）的特征是 c-myc 癌基因的过度表达，而在绝大多数情况下，这种基因的过度表达是 IGH/MYC 易位的结果。虽然 myc 是关键事件，但 BL 是一个由遗传和表观遗传变化组成的复杂混合物，导致编码和非编码转录本的失调。新出现的证据表明，miRNA 对 mRNA 转录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 的改变及其与假定的 mRNA 靶标的相关性尚未得到广泛研究。
方法
我们使用更敏感和特异的转录组深度测序，比较了一组 GC B 细胞和 eBL 肿瘤的已发表的小 miRNA 和长 mRNA。使用 MiRWalk2.0 来鉴定失调 miRNA 的已验证靶基因，这对于理解与 eBL 发展相关的调控网络非常重要。
结果
我们发现 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出一组 MYC 调控基因的富集。基于网络传播的方法和相关的 miRNA-mRNA 表达分析确定了失调的 miRNA，包括 miR-17~95 簇成员及其具有多种致癌特性的靶基因，这些基因对 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，这代表了 eBL 肿瘤细胞中对 DNA 损伤的重要调节因子。这些肿瘤抑制因子是多个上调 miRNA（miR-19b-3p、miR-26a-5p、miR-30b-5p、miR-92a-5p 和 miR-27b-3p）的靶基因，这可以解释它们在 eBL 中的异常表达。
结论
由于 ATM 和 NLK 的 miRNA 介导调节导致 p53 诱导和功能的联合缺失，以及 TFAP4 的上调，可能是人类 miRNA 在 eBL 致癌作用中的核心作用。这促进了IGH/MYC 染色体易位的 eBL 肿瘤细胞的存活，并促进了 MYC 诱导的细胞周期进展，从而启动了 eBL 淋巴瘤的发生。与 GC B 细胞相比，eBL 中 miRNA-mRNA 相互作用的这种特征为 eBL 中 miRNA 介导的转录调节提供了新的见解，这对于新的改进的治疗策略可能是有用的。
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