The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis.
The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis.
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环状RNA circHMGB2通过miR-181a-5p/CARM1轴驱动肺腺癌和鳞状细胞癌的免疫抑制和抗PD-1耐药性
DOI：
10.1186/s12943-022-01586-w
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发表时间：
2022-05-07
期刊：
影响因子：
37.3
通讯作者：
Wu, Yong-Bing
中科院分区：
文献类型：
--
作者：
Zhang, Ling-Xian;Gao, Jian;Long, Xiang;Zhang, Peng-Fei;Yang, Xin;Zhu, Shu-Qiang;Pei, Xu;Qiu, Bai-Quan;Chen, Shi-Wei;Lu, Feng;Lin, Kun;Xu, Jian Jun;Wu, Yong-Bing
先前的研究已经证实了HMGB 2在各种癌症中的致癌作用，但HMGB 2衍生的circRNA的生物学功能仍然未知。因此，我们打算研究HMGB 2衍生的circRNA在肺腺癌（LUAD）和鳞状细胞癌（LUSC）中的潜在作用。使用qRT-PCR评估LUAD和LUSC组织以及匹配的正常组织中HMGB 2衍生的circRNA的表达谱。通过Transwell、CCK-8、流式细胞术和免疫组织化学测定在体外以及在免疫活性小鼠模型和人源化小鼠模型中测定circHMGB 2在LUAD和LUSC进展中的作用。此外，进行了体内circRNA沉淀测定、荧光素酶报告基因测定和RNA下拉测定，以探索circHMGB 2在LUAD和LUSC中促进抗PD-1抗性的潜在机制。circHMGB 2（hsa_circ_0071452）的表达在NSCLC组织中显著上调，并且生存分析将circHMGB 2鉴定为LUAD和LUSC患者中不良预后的独立指标。我们发现，circHMGB 2对LUAD和LUSC细胞的增殖产生了轻微的影响，但circHMGB 2通过在免疫活性小鼠模型和人源化小鼠模型中促进抗肿瘤免疫的耗尽而显著重塑了肿瘤微环境。从机制上讲，circHMGB 2通过海绵状miR-181 a-5 p缓解下游CARM 1的抑制，从而灭活LUAD和LUSC中的1型干扰素应答。此外，我们发现circHMGB 2表达的上调降低了抗PD-1治疗的功效，并且我们揭示了CARM 1抑制剂EZM 2302和抗PD-1抗体的组合在临床前模型中发挥了有希望的协同作用。circHMGB 2过表达主要通过重塑肿瘤微环境和调节LUAD和LUSC患者中的抗PD-1抗性来促进LUAD和LUSC进展。本研究为LUAD和LUSC的治疗提供了新的策略。在线版本包含补充材料，可通过10.1186/s12943-022-01586-w获得。
Previous studies have confirmed the oncogenic role of HMGB2 in various cancers, but the biological functions of HMGB2-derived circRNAs remain unknown. Thus, we intended to investigate the potential role of HMGB2-derived circRNAs in lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). The expression profiles of HMGB2-derived circRNAs in LUAD and LUSC tissues and matched normal tissues were assessed using qRT–PCR. The role of circHMGB2 in the progression of the LUAD and LUSC was determined in vitro by Transwell, CCK-8, flow cytometry and immunohistochemistry assays, as well as in vivo in an immunocompetent mouse model and a humanized mouse model. In addition, in vivo circRNA precipitation assays, luciferase reporter assays and RNA pulldown assays were performed to explore the underlying mechanism by which circHMGB2 promotes anti-PD-1 resistance in the LUAD and LUSC. The expression of circHMGB2 (hsa_circ_0071452) was significantly upregulated in NSCLC tissues, and survival analysis identified circHMGB2 as an independent indicator of poor prognosis in the LUAD and LUSC patients. We found that circHMGB2 exerted a mild effect on the proliferation of the LUAD and LUSC cells, but circHMGB2 substantially reshaped the tumor microenvironment by contributing to the exhaustion of antitumor immunity in an immunocompetent mouse model and a humanized mouse model. Mechanistically, circHMGB2 relieves the inhibition of downstream CARM1 by sponging miR-181a-5p, thus inactivating the type 1 interferon response in the LUAD and LUSC. Moreover, we found that the upregulation of circHMGB2 expression decreased the efficacy of anti-PD-1 therapy, and we revealed that the combination of the CARM1 inhibitor EZM2302 and an anti-PD-1 antibody exerted promising synergistic effects in a preclinical model. circHMGB2 overexpression promotes the LUAD and LUSC progression mainly by reshaping the tumor microenvironment and regulating anti-PD-1 resistance in the LUAD and LUSC patients. This study provides a new strategy for the LUAD and LUSC treatment. The online version contains supplementary material available at 10.1186/s12943-022-01586-w.
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