The identification of microRNAs in a genomically unstable region of human chromosome 8q24
The identification of microRNAs in a genomically unstable region of human chromosome 8q24
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DOI：
10.1158/1541-7786.mcr-07-0105
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发表时间：
2008-02-01
影响因子：
5.2
通讯作者：
Caplen, Natasha J.
中科院分区：
文献类型：
--
作者：
Huppi, Konrad;Volfovsky, Natalia;Caplen, Natasha J.
PVT1 位点被鉴定为 T(2;8) 和 T(8;22)“变体”MYC 激活染色体易位断点簇，在伯基特淋巴瘤 (vBL) 的亚型（约 20%）中延伸至 MYC 下游 400 kb。最近有报道称 microRNA (miRNA) 可能与脆弱位点和癌症相关基因组区域有关，促使我们研究染色体 8q24 上的 PVT1 区域是否可能包含 miRNA。对覆盖 PVT1 位点的基因组序列进行计算分析并进行实验验证，确定了 7 个 miRNA。一种 miRNA hsa-miR-1204 位于先前描述的 PVT1 外显子 (1b) 内，该外显子通常与 vBL 中的免疫球蛋白轻链恒定区融合，并且在 MYC/PVT1 扩增的肿瘤中以高拷贝数存在。与人类对应物一样，小鼠 mmu-miR-1204 代表与 Myc 最接近的 miRNA（类似于 50 kb），并且发现仅位于一组逆转录病毒整合位点下游 1 至 2 kb 处。另一种 miRNA，mmu-miR-1206，接近与小鼠浆细胞瘤和小鼠 Pvt1 外显子 1 相关的一组变异易位断点。与未成熟 B 细胞相比，几乎所有 miRNA 前体转录物在晚期 B 细胞（包括浆细胞瘤和 vBL 细胞系）中的表达水平较高，这表明在淋巴发育和/或淋巴瘤中可能发挥作用。此外，慢病毒载体介导的小鼠前B细胞系中miR-1204前体（人和小鼠）的过度表达增加了Myc的表达。在几种具有 MYC/PVT1 共扩增的上皮癌细胞系中也观察到 hsa-miR-1204 前体的高水平表达，表明这些 miRNA 在肿瘤发生中具有潜在的广泛作用。
The PVT1 locus is identified as a cluster of T(2;8) and T(8;22) "variant" MYC-activating chromosomal translocation breakpoints extending 400 kb downstream of MYC in a subset (approximate to 20%) of Burkitt's lymphoma (vBL). Recent reports that microRNAs (miRNA) may be associated with fragile sites and cancer-associated genomic regions prompted us to investigate whether the PVT1 region on chromosome 8q24 may contain miRNAs. Computational analysis of the genomic sequence covering the PVT1 locus and experimental verification identified seven miRNAs. One miRNA, hsa-miR-1204, resides within a previously described PVT1 exon (1b) that is often fused to the immunoglobulin light chain constant region in vBLs and is present in high copy number in MYC/PVT1-amplified tumors. Like its human counterpart, mouse mmu-miR-1204 represents the closest miRNA to Myc (similar to 50 kb) and is found only 1 to 2 kb downstream of a cluster of retroviral integration sites. Another miRNA, mmu-miR-1206, is close to a cluster of variant translocation breakpoints associated with mouse plasmacytoma and exon 1 of mouse Pvt1. Virtually all the miRNA precursor transcripts are expressed at higher levels in late-stage B cells (including plasmacytoma and vBL cell lines) compared with immature B cells, suggesting possible roles in lymphoid development and/or lymphoma. In addition, lentiviral vector-mediated overexpression of the miR-1204 precursor (human and mouse) in a mouse pre-B-cell line increased expression of Myc. High levels of expression of the hsa-miR-1204 precursor is also seen in several epithelial cancer cell lines with MYC/PVT1 coamplification, suggesting a potentially broad role for these miRNAs in tumorigenesis.