Development of a circadian-related prognostic signature highlights RBM17 as a stemness regulator in liver cancer

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.