Cai Juan, Chen Zhiqiang, Zhang Yao, Wang Jinguo, Zhang Zhengrong, Wu Jindao, Mao Jiading, Zuo Xueliang
Department of Oncology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu 241001, China.
Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu 241001, China.
Mol Ther Oncolytics. 2022 Feb 22;24:755-771. doi: 10.1016/j.omto.2022.02.021. eCollection 2022 Mar 17.
Circular RNAs are a class of highly conserved RNAs with stable covalently closed circular structures. Metabolic reprogramming of cancer cells reshapes the tumor microenvironment and can suppress antitumor immunity. Here, we discovered a novel circular RNA, termed circRHBDD1, which augments aerobic glycolysis and restricts anti-PD-1 therapy in hepatocellular carcinoma (HCC). Mechanistic studies revealed that circRHBDD1 recruits the mA reader YTHDF1 to mRNA and accelerates the translation of PIK3R1 in an mA-dependent manner. EIF4A3-mediated exon back-splicing contributes to the upregulation of circRHBDD1. Moreover, circRHBDD1 is highly expressed in anti-PD-1 responder HCC patients, and targeting circRHBDD1 improves anti-PD-1 therapy in an immune-competent mouse model. Overall, these findings illustrate the metabolic importance of the circRHBDD1/YTHDF1/PIK3R1 axis in HCC and show that suppression of circRHBDD1 may bolster the efficacy of anti-PD-1 therapy for HCC treatment.
环状RNA是一类具有稳定共价闭合环状结构的高度保守RNA。癌细胞的代谢重编程重塑了肿瘤微环境，并可抑制抗肿瘤免疫。在此，我们发现了一种新型环状RNA，称为circRHBDD1，它增强有氧糖酵解并限制肝细胞癌（HCC）中的抗PD-1治疗。机制研究表明，circRHBDD1以m6A依赖的方式招募m6A阅读器YTHDF1至mRNA，并加速PIK3R1的翻译。EIF4A3介导的外显子反向剪接导致circRHBDD1上调。此外，circRHBDD1在抗PD-1反应性HCC患者中高表达，在具有免疫活性的小鼠模型中靶向circRHBDD1可改善抗PD-1治疗。总体而言，这些发现阐明了circRHBDD1/YTHDF1/PIK3R1轴在HCC中的代谢重要性，并表明抑制circRHBDD1可能增强抗PD-1治疗HCC的疗效。
