Rong Zeyin, Xu Jin, Yang Jianhui, Wang Wei, Tang Rong, Zhang Zifeng, Tan Zhen, Meng Qingcai, Hua Jie, Liu Jiang, Zhang Bo, Liang Chen, Yu Xianjun, Shi Si
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Cancer Res. 2024 Dec 16;84(24):4246-4263. doi: 10.1158/0008-5472.CAN-23-3596.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with limited treatment options and poor patient survival. Circular RNAs (circRNA) play crucial regulatory roles in the occurrence and development of various cancers, including PDAC. In this study, using circRNA sequencing of diverse PDAC samples, we identified circRREB1 as an oncogenic circRNA that is significantly upregulated in PDAC and is correlated with an unfavorable patient prognosis. Functionally, loss of circRREB1 markedly inhibited glycolysis and stemness, whereas elevated circRREB1 elicited the opposite effects. Mechanistically, circRREB1 interacted with PGK1, disrupting the association between PTEN and PGK1 and increasing PGK1 phosphorylation to activate glycolytic flux. Moreover, circRREB1 promoted WNT7B transcription by directly interacting with YBX1 and facilitating its nuclear translocation, consequently activating the Wnt/β-catenin signaling pathway to maintain PDAC stemness. Overall, these results highlight circRREB1 as a key regulator of metabolic and stemness properties of PDAC. Significance: CircRREB1 stimulates PGK1 to induce glycolysis and activates the Wnt/β-catenin signaling pathway to maintain stemness in pancreatic cancer, indicating the potential of circRREB1 as a biomarker and therapeutic target.
胰腺导管腺癌（PDAC）是一种致死率很高的肿瘤，治疗选择有限，患者生存率低。环状RNA（circRNA）在包括PDAC在内的各种癌症的发生和发展中发挥着关键的调节作用。在本研究中，通过对不同PDAC样本进行circRNA测序，我们鉴定出circRREB1是一种致癌circRNA，在PDAC中显著上调，且与患者预后不良相关。在功能上，circRREB1缺失显著抑制糖酵解和干性，而circRREB1升高则产生相反的效果。机制上，circRREB1与PGK1相互作用，破坏PTEN与PGK1之间的关联并增加PGK1磷酸化以激活糖酵解通量。此外，circRREB1通过直接与YBX1相互作用并促进其核转位来促进WNT7B转录，从而激活Wnt/β-连环蛋白信号通路以维持PDAC干性。总体而言，这些结果突出了circRREB1作为PDAC代谢和干性特性的关键调节因子。意义：circRREB1刺激PGK1诱导糖酵解并激活Wnt/β-连环蛋白信号通路以维持胰腺癌的干性，表明circRREB1作为生物标志物和治疗靶点的潜力。
