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M2 巨噬细胞来源的外泌体长非编码 RNA AGAP2-AS1 通过降低 microRNA-296 和升高 NOTCH2 增强肺癌放疗免疫。

M2 macrophage-derived exosomal long non-coding RNA AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing microRNA-296 and elevating NOTCH2.

机构信息

Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.

出版信息

Cell Death Dis. 2021 May 10;12(5):467. doi: 10.1038/s41419-021-03700-0.

DOI:10.1038/s41419-021-03700-0
PMID:33972506
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8110970/
Abstract

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.

摘要

长链非编码 RNA (lncRNA) 和 microRNA (miRNA) 在人类疾病中发挥着重要作用。我们旨在确定 lncRNA AGAP2 反义 RNA 1 (AGAP2-AS1)/miR-296/Notch 同源蛋白 2 (NOTCH2) 轴对肺癌进展和放射抵抗的影响。检测了肺癌细胞和放射敏感及放射抵抗患者组织中 AGAP2-AS1、miR-296 和 NOTCH2 的表达，并确定了 AGAP2-AS1 对患者预后的预测作用。诱导 THP-1 细胞并提取外泌体，分别用沉默的 AGAP2-AS1、外泌体、上调 AGAP2-AS1 或下调 miR-296 的外泌体处理肺癌细胞。在不同剂量下对细胞进行放射，并评估细胞的生物学过程。此外，还测定了自然杀伤细胞对肺癌细胞的细胞毒性。验证了 AGAP2-AS1 和 miR-296 之间，以及 miR-296 和 NOTCH2 之间的关系。在放射抵抗患者和肺癌细胞中，AGAP2-AS1 和 NOTCH2 增加，而 miR-296 减少。与亲本细胞相比，放射抵抗细胞的恶性行为得到了促进。抑制 AGAP2-AS1、巨噬细胞衍生的外泌体以及过表达 AGAP2-AS1 或抑制 miR-296 的外泌体促进了放射抵抗肺癌细胞的恶性表型。此外，AGAP2-AS1 负调控 miR-296，而 NOTCH2 是 miR-296 的靶标。M2 巨噬细胞衍生的外泌体 AGAP2-AS1 通过降低 miR-296 和升高 NOTCH2 来增强肺癌的放射免疫。本研究可能有助于肺癌的放射治疗研究。

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