Identification of a Novel Circadian Rhythm-Related Signature for Predicting Prognosis and Therapies in Hepatocellular Carcinoma Based on Bulk and Single-Cell RNA Sequencing

Background. Circadian rhythm disruption involves tumorigenesis and tumor progression. However, the influences of circadian rhythm on the tumor microenvironment (TME) and the prognosis of hepatocellular carcinoma (HCC) are unknown. Methods. Bulk RNA-seq and single-cell RNA-seq from TCGA, ICGC, and GEO were used to comprehensively identify prognostic circadian control cells and circadian rhythm associated genes (CRRGs) using R and Python packages. Besides, the circadian rhythm-related prognostic signature was identified and validated. The biological function, immune infiltration, and therapeutic response associated with circadian rhythm-related (CR) risk were detected. Results. A total of 252 differentially expressed CRRGs in HCC were identified, and HCC with a high CR score revealed poor survival. We annotated 11 major cell types in TME; immune cells (B cells, myeloid, CD4+ cells, CD8+ cells, NK cells, Tregs) with high CR score, and hepatocyte, bio-potent cells, fibroblasts, and endothelial cells with low CR score were identified. Moreover, five CRRGs (RPL29, PFKFB3, RPS7, SLC6A6, and RPLP2) were selected and validated as the prognostic signature in HCC. The risk score was calculated based on the prognostic signature, and patients then were divided into high-risk and low-risk groups according to the median value of the risk score. High risk is linked to several metabolism-related pathways and canonical cancer-related pathways and is negatively associated with immunotherapeutic responses and positively associated with some chemotherapeutic drugs. Conclusion. Our finding provides the novel circadian rhythm-related prognostic signature and represents a novel viable “time-dependent” therapeutic option for HCC treatment.