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.

中文翻译：

---

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

以前的研究已经证实了 HMGB2 在各种癌症中的致癌作用，但 HMGB2 衍生的 circRNA 的生物学功能仍然未知。因此，我们打算研究 HMGB2 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 HMGB2 衍生的 circRNA 的表达谱。circHMGB2 在 LUAD 和 LUSC 进展中的作用通过 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进行了体内测定。此外，体内 circRNA 沉淀测定，进行荧光素酶报告基因分析和 RNA 下拉分析以探索 circHMGB2 促进 LUAD 和 LUSC 中抗 PD-1 抗性的潜在机制。circHMGB2 (hsa_circ_0071452) 在 NSCLC 组织中的表达显着上调，生存分析确定 circHMGB2 是 LUAD 和 LUSC 患者预后不良的独立指标。我们发现 circHMGB2 对 LUAD 和 LUSC 细胞的增殖有轻微的影响，但 circHMGB2 在免疫活性小鼠模型和人源化小鼠模型中通过导致抗肿瘤免疫的耗尽而显着重塑了肿瘤微环境。从机制上讲，circHMGB2 通过海绵化 miR-181a-5p 减轻下游 CARM1 的抑制，从而使 LUAD 和 LUSC 中的 1 型干扰素反应失活。而且，我们发现 circHMGB2 表达的上调降低了抗 PD-1 治疗的疗效，并且我们发现 CARM1 抑制剂 EZM2302 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。circHMGB2 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 耐药性来促进 LUAD 和 LUSC 进展。本研究为 LUAD 和 LUSC 治疗提供了新的策略。circHMGB2 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 耐药性来促进 LUAD 和 LUSC 进展。本研究为 LUAD 和 LUSC 治疗提供了新的策略。circHMGB2 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 耐药性来促进 LUAD 和 LUSC 进展。本研究为 LUAD 和 LUSC 治疗提供了新的策略。