Elevated circASCC3 limits antitumor immunity by sponging miR-432-5p to upregulate C5a in non-small cell lung cancer
Elevated circASCC3 limits antitumor immunity by sponging miR-432-5p to upregulate C5a in non-small cell lung cancer
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DOI：
10.1016/j.canlet.2022.215774
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发表时间：
2022-06-06
期刊：
影响因子：
9.7
通讯作者：
Ding, Jian-Yong
中科院分区：
文献类型：
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作者：
Gao, Jian;Zhang, Ling-Xian;Ding, Jian-Yong
尽管抗程序性细胞死亡1（PD 1）治疗已成为晚期非小细胞肺癌（NSCLC）的一线治疗，但大多数NSCLC患者对抗PD 1治疗无效。本研究旨在探讨非小细胞肺癌中环状RNA（circRNA）表达异常与抗PD 1耐药的关系。采用荧光原位杂交和定量逆转录-聚合酶链反应检测circASCC 3（hsa_circ_0077，495）在NSCLC组织和细胞系中的表达。通过体外和体内研究，揭示了circASCC 3在NSCLC进展和抗PD 1耐药中的功能和机制。与配对正常组织相比，NSCLC中的circASCC 3水平上调。具体而言，circASCC 3表达在来自抗PD 1难治性NSCLC患者的组织中高于来自抗PD 1敏感患者的组织。circASCC 3的过表达增强了NSCLC细胞的恶性表型，并导致免疫抑制微环境。从机制上讲，circASCC 3吸收miR-432- 5 p以增加补体C5 a水平，这增强了NSCLC的进展和功能失调的免疫状态。因此，circASCC 3过表达通过影响NSCLC中的补体系统重塑肿瘤微环境，并提供了克服抗PD 1耐药性的潜在策略。
Although anti-programmed cell death 1 (PD1) treatment has become a first-line therapy for advanced non-small cell lung cancer (NSCLC), most NSCLC patients are refractory to anti-PD1. Here, we aimed to investigate the mechanism of dysregulated circular RNAs (circRNAs) related to anti-PD1 resistance in NSCLC. The expression of circASCC3 (hsa_circ_0077,495) in NSCLC tissues and cell lines was evaluated by fluorescence in situ hybridization and quantitative reverse transcription-polymerase chain reaction. The functions and mechanisms of circASCC3 in NSCLC progression and anti-PD1 resistance were uncovered in vitro and in vivo. The circASCC3 level was upregulated in NSCLC compared with that in paired normal tissues. Specifically, circASCC3 expression was higher in tissues from NSCLC patients with anti-PD1 refractory than in those from patients who sensitive to anti- PD1. Overexpression of circASCC3 enhanced the malignant phenotype of NSCLC cells and led to an immunosuppressive microenvironment. Mechanistically, circASCC3 sponged miR-432-5p to increase complement C5a levels, which enhanced the progression and dysfunctional immune status of NSCLC. Thus, circASCC3 over expression reshapes the tumor microenvironment by impacting the complement system in NSCLC and provides a potential strategy to overcome anti-PD1 resistance.