| First Author | Hanley KL | Year | 2022 |
| Journal | Mol Cancer Res | Volume | 20 |
| Issue | 3 | Pages | 337-349 |
| PubMed ID | 34810213 | Mgi Jnum | J:322317 |
| Mgi Id | MGI:7258245 | Doi | 10.1158/1541-7786.MCR-21-0479 |
| Citation | Hanley KL, et al. (2022) Concurrent Disruption of the Ras/MAPK and NF-kappaB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis. Mol Cancer Res 20(3):337-349 |
| abstractText | The Ras/Erk and NF-kappaB 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 Ikkbeta in mice, which promote Ras/Erk and NF-kappaB 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/Erk and NF-kappaB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver. IMPLICATIONS: We demonstrate here that basal levels of the Ras/MAPK and NF-kappaB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic. |
