多词的整合揭示了ECCDNA在弥漫性大B细胞淋巴瘤中的致癌作用
Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling
影响因子:6.80000
分区:医学2区 Top / 医学：研究与实验2区 肿瘤学2区
发表日期:2024 Aug
作者:
Zijuan Wu, Wei Zhang, Luqiao Wang, Jiayan Leng, Yongle Li, Zhou Fan, Mengtao Zhan, Lei Cao, Yongning Jiang, Yan Jiang, Bing Sun, Jianxin Fu, Jianyong Li, Wenyu Shi, Hui Jin
摘要
促进DNA传感机械激活的一种双链DNA（DSDNA），是一种双链DNA（DSDNA），与各种疾病的进展和预后有关。虽然ECCDNA的作用仍然存在争议，但尚未报道它们在扩散的大B细胞淋巴瘤（DLBCL）中的重要性。圆形DNA测序（Circle-Seq）用于证明ECCDNA在DLBCL，DLBCL，和原子力显微镜中的表达曲线以证明ECCDNA的存在。 CCK-8和SCRNA-SEQ技术被用来揭示EccDNA在STING途径中的激活，从而导致细胞增殖增强。化学治疗药物用于检验以下假说，即DNA损伤诱导ECCDNA的产生，从而激活与CGA无关的STING途径。 GEO数据库用于验证ECCDNA相关基因的预后，并使用动物模型来研究DNA损伤疗法与STING抑制剂在抗肿瘤反应上的协同作用。ECCDNA在DLBCL中广泛表达并与患者的预后相关。 ECCDNA的丰度升高促进了DLBCL的发展。化学治疗药物诱导的DNA损伤触发了ECCDNA的产生，导致以CGAS独立的方式激活了刺激信号传导。此外，抑制sting抑制与顺型素的协同抗肿瘤效应。由DNA损伤诱导的eCCDNA，通过独立于CGA激活STING信号在DLBCL中发挥致癌作用。这一发现提供了一种合理的治疗策略，将化学疗法与靶向刺激相结合。由DNA损伤引起的ECCDNA通过独立于CGAS激活刺激信号在DLBCL中发挥致癌作用。与STING抑制剂的化学治疗药物的联合治疗显着延迟了肿瘤的进展，为DLBCL患者，特别是复发和/或难治（R/R）患者提供了对治疗策略的新见解。
Abstract
Extrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported.Circular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses.EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin.EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING.EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.