The Tissue Bank, Center for Genomic Medicine, and the Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
The Tissue Bank, Center for Genomic Medicine, and the Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Am J Pathol. 2015 May;185(5):1487-99. doi: 10.1016/j.ajpath.2015.01.025.
Nasal natural killer (NK) cell lymphoma (NNL) is an Epstein-Barr virus-associated lymphoma of cytotoxic NK cell origin. The Epstein-Barr virus-encoded miR-BART20-5p inhibits T-bet (TBX21), the master transcription factor of cytotoxic NK cells. To further explore the roles of miRNAs in NNLs, we measured the miRNA expression profiles of 36 NNLs. miR-21, miR-142-3p, miR-126, miR-451, and miR-494-3p were the top five miRNAs with the highest expression levels. By using pathway analysis, we identified associations between all of the five miRNAs with the PTEN-AKT-mTOR pathway, in which PTEN suppresses the oncogenic AKT, and mTOR mediates the oncogenic effects of AKT. YT and NK92 cells derived from NK cell lymphomas were used. miR-494-3p inhibited PTEN with secondary activation of AKT in NK92 cells, and miR-142-3p inhibited RICTOR, a key component of the mTOR complex, with secondary suppression of AKT in YT cells. Significantly, T-bet inhibited the PTEN-AKT-mTOR/RICTOR pathway through induction of PTEN and suppression of RICTOR. Therefore, a molecular circuit of T-bet, PTEN, AKT, and RICTOR is regulated by miR-BART20-5p, miR-494-3p, and miR-142-3p. This circuit is involved in the pathogenesis of NNL. Hence, antagomirs to miR-BART20-5p or miR-494-3p, miR-142-3p mimics, or AKT inhibitors may be useful in NNL therapy.
鼻腔自然杀伤 (NK) 细胞淋巴瘤 (NNL) 是一种与 EBV 相关的细胞毒 NK 细胞起源的淋巴瘤。EBV 编码的 miR-BART20-5p 抑制细胞毒 NK 细胞的主转录因子 T-bet（TBX21）。为了进一步探讨 miRNA 在 NNL 中的作用，我们测量了 36 例 NNL 的 miRNA 表达谱。miR-21、miR-142-3p、miR-126、miR-451 和 miR-494-3p 是表达水平最高的前 5 个 miRNA。通过通路分析，我们确定了这 5 个 miRNA 与 PTEN-AKT-mTOR 通路之间的关联，其中 PTEN 抑制致癌 AKT，mTOR 介导 AKT 的致癌作用。YT 和 NK92 细胞来源于 NK 细胞淋巴瘤。miR-494-3p 在 NK92 细胞中通过抑制 PTEN 引起 AKT 的二级激活，miR-142-3p 在 YT 细胞中通过抑制 mTOR 复合物的关键组成部分 RICTOR 引起 AKT 的二级抑制。重要的是，T-bet 通过诱导 PTEN 和抑制 RICTOR 抑制 PTEN-AKT-mTOR/RICTOR 通路。因此，miR-BART20-5p、miR-494-3p 和 miR-142-3p 调节 T-bet、PTEN、AKT 和 RICTOR 的分子回路。该回路参与了 NNL 的发病机制。因此，miR-BART20-5p 或 miR-494-3p 的反义核苷酸、miR-142-3p 的模拟物或 AKT 抑制剂可能对 NNL 治疗有用。
