Integrated single‐cell transcriptomics reveals the hypoxia‐induced inflammation‐cancer transformation in NASH‐derived hepatocellular carcinoma

作者：Yuan Liang, Rui Zhang, Siddhartha Biswas, Qingfa Bu, Zibo Xu, Lei Qiao, Yan Zhou, Jiaqi Tang, Jinren Zhou, Haoming Zhou, Ling Lü · 发表于：Cell Proliferation · 年份：2023 · DOI：10.1111/cpr.13576 · 被引用次数：40 · 研究领域：Immune cells in cancer、Liver Disease Diagnosis and Treatment、Ferroptosis and cancer prognosis

Abstract Non‐alcoholic fatty liver disease (NAFLD) has emerged as the primary risk factor for hepatocellular carcinoma (HCC), owing to improved vaccination rates of Hepatitis B and the increasing prevalence of metabolic syndrome related to obesity. Although the importance of innate and adaptive immune cells has been emphasized, the malignant transformation of hepatocytes and their intricate cellular network with the immune system remain unclear. The study incorporated four single‐cell transcriptomic datasets of liver tissues covering healthy and NAFLD‐related disease status. To identify the subsets and functions of hepatocytes and macrophages, we employed differential composition analysis, functional enrichment analysis, pseudotime analysis, and scenic analysis. Furthermore, an experimental mouse model for the transformation of nonalcoholic steatohepatitis into hepatocellular carcinoma was established for validation purposes. We defined CYP7A1 + hepatocytes enriched in precancerous lesions as ‘Transitional Cells’ in the progression from NAFLD to HCC. CYP7A1 + hepatocytes upregulated genes associated with stress response, inflammation and cancer‐associated pathways and downregulated the normal hepatocyte signature. We observed that hypoxia activation accompanied the entire process of inflammation‐cancer transformation. Hepatocyte‐derived HIF1A was gradually activated during the progression of NAFLD disease to adapt to the hypoxic microenvironment and hepatocytes under hypoxic ...