PTEN-AKT-mTOR/RICTOR 通路在鼻腔自然杀伤细胞淋巴瘤中被 miR-494-3p 通过 PTEN 激活，被 miR-142-3p 通过 RICTOR 抑制。

The PTEN-AKT-mTOR/RICTOR Pathway in Nasal Natural Killer Cell Lymphoma Is Activated by miR-494-3p via PTEN But Inhibited by miR-142-3p via RICTOR.

机构信息

The Tissue Bank, Center for Genomic Medicine, and the Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.

出版信息

Am J Pathol. 2015 May;185(5):1487-99. doi: 10.1016/j.ajpath.2015.01.025.

DOI:10.1016/j.ajpath.2015.01.025

PMID:25907832

Abstract

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.

摘要

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。