Yan Jingsong, Yang Xiao, Lu Jiabin, Wu Shasha, Wang Yanchen, Du Yuyang, Zheng Jingyi, Wang Fenfen, Gao Han, Yang Hui, Xi Shaoyan, Li Yan
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
Cancer Cell Int. 2025 Jun 13;25(1):211. doi: 10.1186/s12935-025-03843-6.
The liver exhibits extensive circadian regulation among organs. Epidemiological studies have substantiated that disruptions in circadian rhythm constitute a risk factor for the oncogenesis of liver cancer. Nonetheless, the molecular underpinnings of how circadian dysregulation influences liver cancer progression remain elusive. Our research aims to elucidate these mechanisms and develop a predictive model for prognosis and treatment responsiveness. Our multi-omics analysis revealed extensive dysregulation of liver circadian genes (LCGs) in liver cancer. Employing machine learning algorithms, we pinpointed four pivotal dysregulated LCGs. Through the integration of single-cell, bulk, and spatial transcriptomics, we further elucidated the interconnections between LCGs dysregulation and the tumor microenvironment. In vivo and in vitro experiments demonstrated that RBM17, identified as a crucial dysregulated LCG, promotes the progression of liver cancer and cisplatin resistance by facilitating cancer stem cell phenotype. The circadian prognosis scores (CPS), based on these four genes, effectively reflected the prognosis of liver cancer patients and their responses to various therapeutic interventions. Mechanism of Action (MOA) analysis suggested that high CPS level may sensitize tumors to cell cycle-targeted therapies. Collectively, our findings provide new insights into the interplay between liver circadian gene regulation and liver cancer progression, and propose novel therapeutic targets for liver cancer.
肝脏在各器官中表现出广泛的昼夜节律调节。流行病学研究证实，昼夜节律紊乱是肝癌发生的一个危险因素。然而，昼夜节律失调如何影响肝癌进展的分子基础仍不清楚。我们的研究旨在阐明这些机制，并开发一种用于预后和治疗反应性的预测模型。我们的多组学分析揭示了肝癌中肝脏昼夜节律基因（LCGs）的广泛失调。利用机器学习算法，我们确定了四个关键的失调LCGs。通过整合单细胞、批量和空间转录组学，我们进一步阐明了LCGs失调与肿瘤微环境之间的相互联系。体内和体外实验表明，被确定为关键失调LCG的RBM17通过促进癌症干细胞表型来促进肝癌进展和顺铂耐药。基于这四个基因的昼夜节律预后评分（CPS）有效地反映了肝癌患者的预后及其对各种治疗干预的反应。作用机制（MOA）分析表明，高CPS水平可能使肿瘤对细胞周期靶向治疗敏感。总的来说，我们的研究结果为肝脏昼夜节律基因调控与肝癌进展之间的相互作用提供了新的见解，并提出了肝癌的新治疗靶点。
