环状 RNA circHMGB2 通过 miR-181a-5p/CARM1 轴驱动肺腺癌和鳞状细胞癌中的免疫抑制和抗 PD-1 耐药。
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.
机构信息
Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang University, 1 Ming de Road, Nanchang, 330000, Jiangxi, People's Republic of China.
Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai, 200032, People's Republic of China.
出版信息
Mol Cancer. 2022 May 7;21(1):110. doi: 10.1186/s12943-022-01586-w.
BACKGROUND
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).
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
先前的研究已经证实 HMGB2 在各种癌症中的致癌作用，但 HMGB2 衍生 circRNAs 的生物学功能仍不清楚。因此，我们旨在研究 HMGB2 衍生 circRNAs 在肺腺癌 (LUAD) 和鳞状细胞癌 (LUSC) 中的潜在作用。
方法
使用 qRT-PCR 评估 LUAD 和 LUSC 组织及配对正常组织中 HMGB2 衍生 circRNAs 的表达谱。通过 Transwell、CCK-8、流式细胞术和免疫组化检测，以及在免疫功能正常的小鼠模型和人源化小鼠模型中，体外研究 circHMGB2 在 LUAD 和 LUSC 进展中的作用。此外，进行体内 circRNA 沉淀检测、荧光素酶报告基因检测和 RNA 下拉检测，以探讨 circHMGB2 促进 LUAD 和 LUSC 抗 PD-1 耐药的潜在机制。
结果
circHMGB2（hsa_circ_0071452）在 NSCLC 组织中表达显著上调，生存分析确定 circHMGB2 是 LUAD 和 LUSC 患者不良预后的独立指标。我们发现，circHMGB2 对 LUAD 和 LUSC 细胞的增殖影响较小，但通过促进免疫功能正常的小鼠模型和人源化小鼠模型中的抗肿瘤免疫衰竭，circHMGB2 显著重塑了肿瘤微环境。机制上，circHMGB2 通过海绵吸附 miR-181a-5p 来解除下游 CARM1 的抑制作用，从而使 LUAD 和 LUSC 中的 I 型干扰素反应失活。此外，我们发现 circHMGB2 表达上调降低了抗 PD-1 治疗的疗效，并且我们揭示了 CARM1 抑制剂 EZM2302 与抗 PD-1 抗体联合在临床前模型中具有有前景的协同作用。
结论
circHMGB2 的过表达主要通过重塑肿瘤微环境和调节 LUAD 和 LUSC 患者的抗 PD-1 耐药来促进 LUAD 和 LUSC 的进展。本研究为 LUAD 和 LUSC 的治疗提供了新策略。
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