MicroRNA-mediated down-regulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells:: A potential pathogenetic lesion in Hodgkin lymphomas
MicroRNA-mediated down-regulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells:: A potential pathogenetic lesion in Hodgkin lymphomas
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DOI：
10.2353/ajpath.2008.080009
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发表时间：
2008-07-01
影响因子：
6
通讯作者：
Tam, Wayne
中科院分区：
文献类型：
--
作者：
Nie, Kui;Gomez, Mario;Tam, Wayne
PRDM1/Blimp-1 是 B 细胞终末分化的主要调节因子，最近被确定为激活 B 细胞类型的弥漫性大 B 细胞淋巴瘤突变失活的肿瘤抑制靶点。我们的研究表明，在霍奇金淋巴瘤 (HL) 的霍奇金/里德-斯滕伯格 (HRS) 细胞中，PRDM1/blimp-1 也是 miR-9 和 let-7a 介导的 microRNA (miRNA) 介导的下调靶标。通过直接 miRNA 克隆进行的 miRNA 表达谱分析表明，这两种 miRNA 都是培养的 HRS 细胞中表达量最高的。这些 miRNA 功能性地靶向 PRDM1/blimp-1 mRNA 3' 非翻译区的特定结合位点，并通过抑制翻译来抑制荧光素酶报告基因活性。此外，HL 细胞系中高水平的 miR-9 和 let-7a 与低水平的 PRDM1/Blimp-1 相关。与体外对应物类似，原发性 HL 病例中的大多数 HRS 细胞表现出弱 PRDM1/Blimp-1 表达或无 PRDM1/Blimp-1 表达。 miR-9或let-7a的过度表达使U266细胞中的PRDM1/Blimp-1水平降低了30%至50%，而在L428细胞中同时抑制它们的活性导致PRDM1/Blimp-1的诱导约2.6倍。 miRNA 介导的 PRDM1/Blimp-1 下调可能通过干扰正常 B 细胞终末分化来促进 HRS 细胞的表型维持和发病机制，从而代表一种新的分子病变，也是 HL 的潜在治疗靶点。
PRDM1/Blimp-1, a master regulator in terminal B-cell differentiation, has been recently identified as a tumor suppressor target for mutational inactivation in diffuse large B-cell lymphomas of the activated B-cell type. Our studies here demonstrate that PRDM1/blimp-1 is also a target for microRNA (miRNA)-mediated down-regulation by miR-9 and let-7a in Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL). MiRNA expression profiling by direct miRNA cloning demonstrated that both of these miRNAs are among the most highly expressed in cultured HRS cells. These miRNAs functionally targeted specific binding sites in the 3' untranslated region of PRDM1/blimp-1 mRNA and repressed luciferase reporter activities through repression of translation. In addition, high levels of miR-9 and let-7a in HL cell lines correlated with low levels of PRDM1/Blimp-1. Similar to their in vitro counterparts, the majority of HRS cells in primary HL cases showed weak or no PRDM1/Blimp-1 expression. Over-expression of miR-9 or let-7a reduced PRDM1/Blimp-1 levels in U266 cells by 30% to 50%, whereas simultaneous inhibition of their activities in L428 cells resulted in an approximately 2.6-fold induction in PRDM1/Blimp-1. MiRNA-mediated down-regulation of PRDM1/Blimp-1 may contribute to the phenotype maintenance and pathogenesis of HRS cells by interfering with normal B-cell terminal differentiation, thus representing a novel molecular lesion, as well as a potential therapeutic target in HL.