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外泌体miR-181a的沉默逆转小儿急性淋巴细胞白血病细胞增殖。

Silencing of Exosomal miR-181a Reverses Pediatric Acute Lymphocytic Leukemia Cell Proliferation.

作者信息

Haque Shabirul, Vaiselbuh Sarah R

机构信息

Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.

Department of Pediatrics, Staten Island University Hospital, Northwell Health, 475 Seaview Ave, Staten Island, NY 10305, USA.

出版信息

Pharmaceuticals (Basel). 2020 Sep 11;13(9):241. doi: 10.3390/ph13090241.

DOI:10.3390/ph13090241
PMID:32932883
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7558769/
Abstract

Exosomes are cell-generated nano-vesicles found in most biological fluids. Major components of their cargo are lipids, proteins, RNA, DNA, and non-coding RNAs. The miRNAs carried within exosomes reveal real-time information regarding disease status in leukemia and other cancers, and therefore exosomes have been studied as novel biomarkers for cancer. We investigated the impact of exosomes on cell proliferation in pediatric acute lymphocytic leukemia (PALL) and its reversal by silencing of exo-miR-181a. We isolated exosomes from the serum of PALL patients (Exo-PALL) and conditioned medium of leukemic cell lines (Exo-CM). We found that Exo-PALL promotes cell proliferation in leukemic B cell lines by gene regulation. This exosome-induced cell proliferation is a precise event with the up-regulation of proliferative (PCNA, Ki-67) and pro-survival genes (MCL-1, and BCL2) and suppression of pro-apoptotic genes (BAD, BAX). Exo-PALL and Exo-CM both show over expression of miR-181a compared to healthy donor control exosomes (Exo-HD). Specific silencing of exosomal miR-181a using a miR-181a inhibitor confirms that miR-181a inhibitor treatment reverses Exo-PALL/Exo-CM-induced leukemic cell proliferation in vitro. Altogether, this study suggests that exosomal miR-181a inhibition can be a novel target for growth suppression in pediatric lymphatic leukemia.

摘要

外泌体是在大多数生物体液中发现的细胞产生的纳米囊泡。其主要成分包括脂质、蛋白质、RNA、DNA和非编码RNA。外泌体中携带的微小RNA（miRNA）揭示了白血病和其他癌症疾病状态的实时信息，因此外泌体已被作为癌症的新型生物标志物进行研究。我们研究了外泌体对小儿急性淋巴细胞白血病（PALL）细胞增殖的影响以及通过沉默外泌体miR-181a对其的逆转作用。我们从PALL患者的血清（Exo-PALL）和白血病细胞系的条件培养基（Exo-CM）中分离出外泌体。我们发现Exo-PALL通过基因调控促进白血病B细胞系的细胞增殖。这种外泌体诱导的细胞增殖是一个精确的过程，增殖相关基因（增殖细胞核抗原PCNA、Ki-67）和促生存基因（髓细胞白血病-1 MCL-1、B细胞淋巴瘤/白血病-2 BCL2）上调，促凋亡基因（BAD、BAX）受到抑制。与健康供体对照外泌体（Exo-HD）相比，Exo-PALL和Exo-CM均显示miR-181a过表达。使用miR-181a抑制剂对外泌体miR-181a进行特异性沉默证实，miR-181a抑制剂处理可在体外逆转Exo-PALL/Exo-CM诱导的白血病细胞增殖。总之，本研究表明抑制外泌体miR-181a可能是小儿淋巴细胞白血病生长抑制的新靶点。

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