Department of Pathology, National University Health System, Singapore.
Blood. 2011 Nov 3;118(18):4919-29. doi: 10.1182/blood-2011-07-364224. Epub 2011 Sep 14.
We performed a comprehensive genome-wide miRNA expression profiling of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed paraffin-embedded tissue (n = 30) and NK cell lines (n = 6) compared with normal NK cells, with the objective of understanding the pathogenetic role of miRNA deregulation in NKTL. Compared with normal NK cells, differentially expressed miRNAs in NKTL are predominantly down-regulated. Re-expression of down-regulated miRNAs, such as miR-101, miR-26a, miR26b, miR-28-5, and miR-363, reduced the growth of the NK cell line and modulated the expression of their predicted target genes, suggesting the potential functional role of the deregulated miRNAs in the oncogenesis of NKTL. Taken together, the predicted targets whose expression is inversely correlated with the expression of deregulated miRNA in NKTL are significantly enriched for genes involved in cell cycle-related, p53, and MAPK signaling pathways. We also performed immunohistochemical validation for selected target proteins and found overexpression of MUM1, BLIMP1, and STMN1 in NKTL, and notably, a corresponding increase in MYC expression. Because MYC is known to cause repression of miRNA expression, it is possible that MYC activation in NKTL may contribute to the suppression of the miRNAs regulating MUM1, BLIMP1, and STMN1.
我们使用福尔马林固定石蜡包埋组织（n=30）和 NK 细胞系（n=6）对结外鼻型自然杀伤/T 细胞淋巴瘤（NKTL）进行了全面的全基因组 miRNA 表达谱分析，与正常 NK 细胞进行比较，旨在了解 miRNA 失调在 NKTL 发病机制中的作用。与正常 NK 细胞相比，NKTL 中差异表达的 miRNA 主要下调。下调 miRNA 的重新表达，如 miR-101、miR-26a、miR26b、miR-28-5 和 miR-363，可降低 NK 细胞系的生长并调节其预测靶基因的表达，表明失调 miRNA 在 NKTL 发生中的潜在功能作用。综上所述，在 NKTL 中与失调 miRNA 的表达呈负相关的预测靶基因的表达显著富集了与细胞周期相关、p53 和 MAPK 信号通路相关的基因。我们还对选定的靶蛋白进行了免疫组织化学验证，发现 NKTL 中存在 MUM1、BLIMP1 和 STMN1 的过表达，值得注意的是，MYC 表达也相应增加。因为已知 MYC 会导致 miRNA 表达的抑制，所以在 NKTL 中 MYC 的激活可能导致调节 MUM1、BLIMP1 和 STMN1 的 miRNA 受到抑制。
