Institute of Microbiology and Hygiene, Department of Virology, University Hospital of Saarland University, Homburg/Saar, Germany.
PLoS One. 2012;7(8):e42193. doi: 10.1371/journal.pone.0042193. Epub 2012 Aug 3.
The Epstein-Barr virus (EBV) is an oncogenic human Herpes virus involved in the pathogenesis of nasal NK/T-cell lymphoma. EBV encodes microRNAs (miRNAs) and induces changes in the host cellular miRNA profile. MiRNAs are short non-coding RNAs of about 19-25 nt length that regulate gene expression by post-transcriptional mechanisms and are frequently deregulated in human malignancies including cancer. The microRNA profiles of EBV-positive NK/T-cell lymphoma, non-infected T-cell lymphoma and normal thymus were established by deep sequencing of small RNA libraries. The comparison of the EBV-positive NK/T-cell vs. EBV-negative T-cell lymphoma revealed 15 up- und 16 down-regulated miRNAs. In contrast, the majority of miRNAs was repressed in the lymphomas compared to normal tissue. We also identified 10 novel miRNAs from known precursors and two so far unknown miRNAs. The sequencing results were confirmed for selected miRNAs by quantitative Real-Time PCR (qRT-PCR). We show that the proinflammatory cytokine interleukin 1 alpha (IL1A) is a target for miR-142-3p and the oncogenic BCL6 for miR-205. MiR-142-3p is down-regulated in the EBV-positive vs. EBV-negative lymphomas. MiR-205 was undetectable in EBV-negative lymphoma and strongly down-regulated in EBV-positive NK/T-cell lymphoma as compared to thymus. The targets were confirmed by reporter assays and by down-regulation of the proteins by ectopic expression of the cognate miRNAs. Taken together, our findings demonstrate the relevance of deregulated miRNAs for the post-transcriptional gene regulation in nasal NK/T-cell lymphomas.
EB 病毒（EBV）是一种致癌的人类疱疹病毒，参与了鼻腔 NK/T 细胞淋巴瘤的发病机制。EBV 编码 microRNAs（miRNAs），并诱导宿主细胞 miRNA 谱的变化。miRNAs 是长度约为 19-25nt 的短非编码 RNA，通过转录后机制调节基因表达，并且在包括癌症在内的人类恶性肿瘤中经常失调。通过对小 RNA 文库进行深度测序，建立了 EBV 阳性 NK/T 细胞淋巴瘤、未感染 T 细胞淋巴瘤和正常胸腺的 miRNA 图谱。EBV 阳性 NK/T 细胞与 EBV 阴性 T 细胞淋巴瘤的比较显示，有 15 个上调和 16 个下调的 miRNA。相比之下，与正常组织相比，大多数 miRNA 在淋巴瘤中受到抑制。我们还从已知前体中鉴定出 10 个新的 miRNA 和两个迄今未知的 miRNA。通过定量实时 PCR（qRT-PCR）对选定的 miRNA 进行了测序结果验证。我们表明，促炎细胞因子白细胞介素 1 阿尔法（IL1A）是 miR-142-3p 的靶标，致癌基因 BCL6 是 miR-205 的靶标。miR-142-3p 在 EBV 阳性与 EBV 阴性淋巴瘤中下调。miR-205 在 EBV 阴性淋巴瘤中无法检测到，并且在 EBV 阳性 NK/T 细胞淋巴瘤中与胸腺相比强烈下调。通过报告基因实验和通过外源表达同源 miRNA 下调蛋白证实了这些靶标。总之，我们的研究结果表明，失调的 miRNAs 对于鼻腔 NK/T 细胞淋巴瘤的转录后基因调控具有重要意义。
