Exosomal lncRNA HMMR-AS1 mediates macrophage polarization through miR-147a/ARID3A axis under hypoxia and affects the progression of hepatocellular carcinoma

IF 4.4 3区医学 Q2 ENVIRONMENTAL SCIENCES

Environmental Toxicology Pub Date : 2022-02-18 DOI:10.1002/tox.23489

Xu Wang, Yao Zhou, Ke Dong, Hao Zhang, Jun Gong, Shan Wang

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引用次数: 25

Abstract

Background

At present, the role of lncRNA in different kinds of tumors has been widely reported, but its role with hypoxic environment and macrophage polarization is still unclear. Therefore, this study tried to clarify the role of exosomal lncRNA in tumor hypoxic environment and macrophage polarization in the process of hepatocellular carcinoma (HCC), and provide a basis for targeted therapy of HCC.

Methods

Bioinformatics screening of differentially expressed lncRNA and mRNA was carried out through GEO database, and the expression of lncRNA HMMR-AS1 in tumor tissues was detected and verified in HCC tissues. The effects of HMMR-AS1 on proliferation, migration, apoptosis, and macrophage polarization were determined by in vitro and in vivo experiments. Perform luciferase reporter gene detection and RNA immunoprecipitation to reveal the interaction between HMMR-AS1, miR-147a, and ARID3A. At the same time, the JASPAR database and dual luciferase report were used to detect the relationship between HIF-1α and HMMR-AS1 transcription regulation. Finally, nanoparticle tracking technology, transmission electron microscopy, and western blot were used to detect the effect of hypoxic environment on exosome secretion.

Results

LncRNA HMMR-AS1 was significantly up-regulated in HCC tissues and HCC cells and was related to the poor prognosis. Inhibiting the expression of HMMR-AS1 could significantly inhibit tumor growth in vitro and in vivo. Further study of the mechanism showed that HMMR-AS1 could competitively bind to miR-147a to prevent the degradation of ARID3A. Exosomes carrying HMMR-AS1 could promote the M2 polarization of macrophages mediated by this pathway and further accelerate the progression of HCC. In addition, in the hypoxic environment, HIF-1α promotes its transcription by binding to the HMMR-AS1 promoter and induces an increase in the number of exosomes secreted.

Conclusion

In summary, we first discovered and verified the role of lncRNA HMMR-AS1 in HCC. In terms of mechanism, the promotion of exosomal HMMR-AS1 competitive adsorption of miR-147a under hypoxic environment affects ARID3A-mediated macrophage polarization. These data provide a new direction for the research on the pathogenesis of HCC and the development of targeted therapy.

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外泌体lncRNA HMMR-AS1在缺氧条件下通过miR-147a/ARID3A轴介导巨噬细胞极化，影响肝癌的进展

目前，lncRNA在不同类型肿瘤中的作用已被广泛报道，但其在缺氧环境和巨噬细胞极化中的作用尚不清楚。因此，本研究试图阐明外泌体lncRNA在肝癌发生过程中肿瘤缺氧环境和巨噬细胞极化中的作用，为肝癌的靶向治疗提供依据。方法通过GEO数据库对差异表达的lncRNA和mRNA进行生物信息学筛选，检测并验证肝癌组织中lncRNA HMMR-AS1在肿瘤组织中的表达。通过体外和体内实验研究HMMR-AS1对巨噬细胞增殖、迁移、凋亡和极化的影响。荧光素酶报告基因检测和RNA免疫沉淀，揭示hmr - as1、miR-147a和ARID3A之间的相互作用。同时利用JASPAR数据库和双荧光素酶报告检测HIF-1α与hmr - as1转录调控的关系。最后，采用纳米颗粒跟踪技术、透射电镜和western blot检测低氧环境对外泌体分泌的影响。结果LncRNA HMMR-AS1在HCC组织和HCC细胞中表达显著上调，并与预后不良有关。抑制HMMR-AS1的表达可显著抑制肿瘤在体内和体外的生长。进一步的机制研究表明，hmr - as1可以竞争性地结合miR-147a，从而阻止ARID3A的降解。携带HMMR-AS1的外泌体可促进该途径介导的巨噬细胞M2极化，进一步加速HCC的进展。此外，在缺氧环境下，HIF-1α通过结合HMMR-AS1启动子促进其转录，诱导分泌的外泌体数量增加。综上所述，我们首次发现并验证了lncRNA HMMR-AS1在HCC中的作用。在机制上，缺氧环境下促进外泌体HMMR-AS1竞争性吸附miR-147a影响arid3a介导的巨噬细胞极化。这些数据为HCC发病机制的研究和靶向治疗的发展提供了新的方向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Environmental Toxicology 环境科学-毒理学

CiteScore

7.10

自引率

8.90%

发文量

261

审稿时长

4.5 months

期刊介绍： The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.