Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.
NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
Signal Transduct Target Ther. 2023 Feb 1;8(1):48. doi: 10.1038/s41392-022-01224-3.
In the treatment of most malignancies, radiotherapy plays a significant role. However, the resistance of cancer cells to ionizing radiation (IR) is the main reason for the failure of radiotherapy, which causes tumor recurrence and metastasis. In this study, we confirmed that GPR162, an orphan receptor in the G-protein-coupled receptor family, acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes (STING), which targeted DNA damage responses, activated IRF3, accelerated the activation of type I interferon system, promoted the expression of chemokines including CXCL10 and CXCL4, and inhibited the occurrence and development of tumors. Interestingly, the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS. STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models. In addition, most solid tumors showed low expression of GPR162. And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma, liver cancer, breast cancer, etc. In summary, these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response, providing an alternative strategy for improving cancer radiotherapy.
在大多数恶性肿瘤的治疗中，放射治疗起着重要的作用。然而，癌细胞对电离辐射（IR）的抵抗力是放射治疗失败的主要原因，导致肿瘤复发和转移。在这项研究中，我们证实孤儿 G 蛋白偶联受体家族中的 GPR162 通过与干扰素基因刺激物（STING）相互作用，充当新型放射治疗增敏剂，靶向 DNA 损伤反应，激活 IRF3，加速 I 型干扰素系统的激活，促进趋化因子（包括 CXCL10 和 CXCL4）的表达，抑制肿瘤的发生和发展。有趣的是，GPR162 过表达激活 STING 不依赖于 cGAS 的经典途径。STING 抑制剂可以抵抗 GPR162 过表达在 IR 诱导的小鼠模型中的抗肿瘤作用。此外，大多数实体瘤表现出低水平的 GPR162 表达。而 GPR162 表达水平较高则表明肺腺癌、肝癌、乳腺癌等患者的预后较好。综上所述，这些结果表明，GPR162 可能通过促进放射治疗诱导的 STING-IFN 产生和增加趋化因子（包括 CXCL10 和 CXCL4）的表达来增强放射治疗的敏感性，为改善癌症放射治疗提供了一种替代策略。
