Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model.

BACKGROUND & AIMS

Chronic circadian dysfunction increases the risk of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) but the underlying mechanisms and direct relevance to human HCC are not established. This study is to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression.

METHODS

Chronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of humanized HCC was analyzed by biomarker, pathological/histological, genetic, RNAseq, metabolomic, and integrated bioinformatic analyses.

RESULTS

Circadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human HCC metastasis independent of diet choice in a humanized mouse model. The deregulated transcriptomes in necrotic-inflammatory humanized livers and HCCs bear striking resemblances to those of human non-alcoholic steatohepatitis (NASH), cirrhosis, and HCCs. Stable circadian entrainment of hosts rhythmically paces NASH and HCC transcriptomes to decrease HCC incidence and prevent HCC metastasis. Circadian disruption directly reprograms NASH and HCC transcriptomes to drive a rapid progression from hepatocarcinogenesis to HCC metastasis. Human hepatocyte and tumour transcripts are clearly distinguishable from mouse transcripts in non-parenchymal cells and tumour stroma and display dynamic changes in metabolism, inflammation, angiogenesis, and oncogenic signaling in NASH, progressing to hepatocyte malignant transformation and immunosuppressive tumour stroma in HCCs. Metabolomic analysis defines specific bile acids as prognostic biomarkers that change dynamically during hepatocarcinogenesis and in response to circadian disruption at all disease stages.

CONCLUSION

Chronic circadian dysfunction is an independent carcinogen to human hepatocytes. Mice with humanized livers provide a powerful preclinical model for studying the impact of the necrotic-inflammatory liver environment and neuroendocrine circadian dysfunction in hepatocarcinogenesis and anti-HCC therapy. IMPACT AND IMPLICATIONS-2: Human epidemiological studies have linked chronic circadian dysfunction to increased HCC risk, but direct evidence that circadian dysfunction is a human carcinogen has not been established. Here we show that circadian dysfunction induces nonalcoholic steatohepatitis (NASH)-related carcinogenesis from human hepatocytes in a murine humanized liver model following the same molecular and pathologic pathways observed in human patients. The gene expression signatures of humanized HCC transcriptomes from circadian disrupted mice closely match those of human HCC with the poorest prognostic outcomes, while those from stably circadian entrained mice match those from human HCC with the best prognostic outcomes. Our studies open a new model for defining to the mechanism of NASH-related HCC and highlight the importance of circadian biology in HCC prevention and treatment.

Informations de copyright

Copyright © 2023. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare no conflicts of interest.