AUTHOR=Wang Rui-Qi , Cui Wei , Cai Jiayi , Sun Yihao 

TITLE=Integrative analysis indicates the prognostic value of circadian rhythm disruption in liver cancer: Potential for therapeutic targeting

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1011264

DOI=10.3389/fimmu.2022.1011264

ISSN=1664-3224

ABSTRACT=Circadian rhythms regulate various biological processes, such as cell division and metabolism. Circadian rhythm disruption (CRD) is often associated with malignant tumor progression and poor prognosis. However, the effect of CRD on liver cancer prognosis has not been systematically analyzed or fully elucidated. Here, we developed a method to quantify and assess intratumoral CRD in a single-cell transcriptomic analysis of liver cancer. We found that malignant cells had higher levels of CRD scores than normal cells. Additionally, malignant cells with high levels of CRD scores were enriched in certain metabolic pathways, such as fatty acid metabolism and the trichloroacetic acid cycle, with higher levels in hepatitis C virus-positive samples. Intercellular communication analysis suggested that CRD regulates chemokine-mediated interactions. We further verified these findings using bulk transcriptomic datasets. We determined that LiverCRD scores were significantly correlated with macrophage infiltration levels and can therefore guide targeted strategies for immunotherapy and chemotherapy. In addition, LiverCRD is also associated with the mutational landscape—for example, TP53 mutation frequency was higher in high-CRD samples. Finally, we constructed a 14-gene-based LASSO-Cox regression model that accurately predicted overall patient survival across multiple datasets, suggesting that CRD may serve as a potential prognostic indicator. Our results may be useful for guiding targeted antitumor strategies.