Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Putian University, Putian, 351100, Fujian, China.
Biochem Biophys Res Commun. 2023 Nov 12;681:106-110. doi: 10.1016/j.bbrc.2023.09.073. Epub 2023 Sep 25.
The global incidence of pancreatic cancer is associated with a high mortality rate and one of the lowest survival rates among all types of cancer. The clinical management modalities for pancreatic cancer encompass surgical intervention, chemotherapy, radiation therapy, targeted therapy, immunotherapy, or a combination thereof. Nevertheless, the diagnosis of pancreatic cancer often occurs at an advanced stage, thereby restricting treatment options and diminishing the prospects of achieving a cure. The cGAS-STING pathway has emerged as a potential target for antitumor therapy due to its role in promoting immune responses against cancer cells. Activation of the cGAS-STING pathway in tumor cells can lead to the production of pro-inflammatory cytokines and type I interferons, which can enhance the recruitment and activation of immune cells to the tumor microenvironment. The cGAS protein was detected in only a half of tumor tissues in pancreatic cancer patients and the underlying mechanism is still elusive. In this study, we have identified the E3 ligase DTX3L as a key regulator of cGAS-STING signaling in pancreatic cancer cells by mediating the ubiquitination and degradation of cGAS. The expression levels of DTX3L were found to be upregulated in pancreatic tumor tissues and correlated with a poor prognosis for patients with pancreatic cancer. Silencing of DTX3L resulted in enhanced activation of the cGAS-STING signaling pathway and improved antitumor immunity for pancreatic cancer, suggesting that targeting the DTX3L-cGAS axis could hold promise for the treatment of this disease.
全球范围内胰腺癌的发病率与高死亡率相关，并且是所有癌症类型中存活率最低的癌症之一。胰腺癌的临床治疗方式包括手术干预、化疗、放疗、靶向治疗、免疫治疗或联合治疗。然而，胰腺癌的诊断往往发生在晚期，从而限制了治疗选择并降低了治愈的可能性。cGAS-STING 通路已成为抗肿瘤治疗的潜在靶点，因为它在促进针对癌细胞的免疫反应方面发挥作用。肿瘤细胞中 cGAS-STING 通路的激活可导致促炎细胞因子和 I 型干扰素的产生，从而增强免疫细胞向肿瘤微环境的募集和激活。在胰腺癌患者的肿瘤组织中仅检测到一半的 cGAS 蛋白，其潜在机制仍不清楚。在这项研究中，我们通过介导 cGAS 的泛素化和降解，确定了 E3 连接酶 DTX3L 是胰腺癌细胞中 cGAS-STING 信号的关键调节剂。发现 DTX3L 的表达水平在胰腺肿瘤组织中上调，并与胰腺癌患者的预后不良相关。沉默 DTX3L 可增强 cGAS-STING 信号通路的激活并改善胰腺癌的抗肿瘤免疫，表明靶向 DTX3L-cGAS 轴可能为治疗这种疾病提供希望。
