Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

ABSTRACT: The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Er

SUBMITTER: Hanley KL 

PROVIDER: S-EPMC8898265 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature