Research progress in the roles of exosomal miRNA in leukemia

doi:10.3969/j.issn.2095-4344.1693

Abstract

Abstract:

BACKGROUND: Exosomes, known as vehicles for substance transporting and signaling communication, are nanosized bilayer-lipid membrane microvesicles secreted by living cell types that harbor biological constituents such as nucleic acids (DNA, mRNA and microRNA) proteins and lipids derived from host cells, which can potentially transfer their cargo through the extracellular fluid to the other cells at distance. Leukemia is a deadly hematologic malignancy. Recent studies have demonstrated that exosomal miRNAs protected from enzymatic degradation (RNase) by the lipid-bilayer membrane are associated with the invasion as well as metastasis in leukemia.
OBJECTIVE: To review the role of exosomal miRNA in leukemia, providing important information on exploring the molecular pathogenesis and targets for diagnosis and treatment of leukemia.
METHODS: PubMed and WanFang databases were retrieved for articles concerning leukemia and exosomal miRNA published from November 2003 to May 2018.The key words were “exosomes, leukemia, miRNAs” in English and Chinese, respectively. Forty-eight eligible articles were included in final analysis.
RESULTS AND CONCLUSION: Exogenous miRNAs enhance the malignant biological behaviors such as survival, proliferation and migration of leukemia cells by acclimating the hematopoietic microenvironment. We can extend the concept of treating leukemia by interfering with the production and release of exogenous miRNAs, blocking the uptake of exogenous miRNAs by the recipient cells and interfering with their target genes. In-depth study on the role of exogenous miRNAs in leukemia is helpful to provide important information for mining diagnostic and therapeutic targets.

Key words: leukemia, exosomes, miRNA, hematopoietic microenvironment, target gene, biomarkers, National Natural Science Foundation of China

CLC Number:

Zhang Juanjuan, Li Ruiwei, He Jigang, Sa Yalian. Research progress in the roles of exosomal miRNA in leukemia[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(17): 2776-2781.

Figures/Tables 1

2.1 外泌体源miRNA与血管新生白血病细胞的浸润转移与肿瘤微环境中的内皮细胞、成纤维细胞、间充质干细胞、基质等成分有关，其中内皮细胞是血管新生的关键成员。已有的研究表明，外泌体源miRNA在白血病细胞与内皮细胞对话中扮演着重要角色，介导骨髓血管化。Tadokoro等[12]报道，在低氧环境(体积分数为1%O2，24 h)中，白血病K562细胞释放富载miR-210的外泌体增多，通过下调抑制血管生成靶基因(ephrin A3、EFNA3)在脐带血管内皮细胞中的表达，从而促进管腔样结构的形成，见表1。研究发现白血病细胞株K562细胞源外泌体富集表达miR-92a，通过Cy3标记pre-miR-92a转染的K562细胞与脐带血管内皮细胞共培养，结果下调了miR-92a靶基因整合素α5在血管内皮细胞中的表达，使内皮细胞的黏附性下降，而迁移以及形成管腔样结构的能力增强[13]，见表1。Paggetti等[14]观察到内皮细胞摄取慢性淋巴细胞白血病源外泌体后，形成管腔样结构的能力增强，其机制与外泌体富载miR-146a、miR-150、miR-155的调控作用有关。Taverna等[15-16]观察到慢性髓系白血病患者血液、LAMA84细胞株培养上清来源外泌体富载miR-126，其呈剂量依赖性上调细胞间黏附分子、血管细胞黏附分子和白细胞介素8在脐带血管内皮细胞的表达，而下调E-cadherin和β-catenin的表达，从而使脐带血管内皮细胞迁移能力以及形成管腔样结构的能力增强，见表1。人类嗜T细胞白血病Ⅰ型病毒(HTLV-Ⅰ)是成人T细胞白血病的致病因子，其编码的TAX蛋白可与IKB激酶γ(IKKγ)直接结合，使NF-κB通路中抑制性蛋白IKB降解，从而使NF-κB通路活化，使细胞抗凋亡的能力增强，发挥促癌作用。El-Saghir等[17]研究表明，成人型T细胞白血病/淋巴瘤细胞C81和HuT-102源外泌体富载致癌因子病毒源TAX蛋白，其中HuT-102细胞源外泌体还携载有miR-21、miR-155和血管内皮生长因子，由骨髓间充质干细胞摄取后活化NF-κB信号通路，调控细胞增殖迁移、抵抗凋亡和促血管形成基因的表达，见表1。骨髓来源的抑制性细胞有免疫抑制作用，促进肿瘤的发生发展。Bruns等[18]报道，慢性淋巴细胞白血病外泌体携载的miR-155诱导骨髓来源的抑制性细胞增多，参与肿瘤的浸润转移和血管形成等病理过程。总而言之，外泌体源miRNA介导白血病细胞的浸润转移和血管形成等病理过程，干预外泌体源miRNA可能是治疗白血病的新思路。"

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