ArticleHepatology (Baltimore, Md.)2018
C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer.
Article in Hepatology (Baltimore, Md.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 40 citations in OpenAlex.
- Resveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism.International journal of molecular sciences · 2026Article
- Relationship Between Total Parenteral Nutrition, Ventilation, and Hepatoblastoma: A Study of 258,929 Neonatal Intensive Care Unit Admissions.Pediatric blood & cancer · 2025Article
- Small-molecule-based targeted therapy in liver cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Genetic Ablation of C/EBPα-p300 Pathway Blocks Development of Obese Pregnancy Associated Liver Disorders in Offspring.Cellular and molecular gastroenterology and hepatology · 2024Article
- Second Generation Small Molecule Inhibitors of Gankyrin for the Treatment of Pediatric Liver Cancer.Cancers · 2022Article
- In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling.Cancers · 2021Review
- The differential expression of perilipin-2 in hepatoblastoma and its association with prognosis.Histology and histopathology · 2021Article
- Olaparib Inhibits Tumor Growth of Hepatoblastoma in Patient-Derived Xenograft Models.Hepatology (Baltimore, Md.) · 2021Article
- RANBP2 ActivatesCancers · 2021Article
- Article
- Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.Nature communications · 2021Article
- miR-10b-5p Suppresses the Proliferation and Invasion of Primary Hepatic Carcinoma Cells by Downregulating EphA2.BioMed research international · 2021Article
- Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment.Frontiers in oncology · 2021Review
- Help for Sick Kids: New Insights Into Hepatoblastoma.Cellular and molecular gastroenterology and hepatology · 2021Article
- The EGFR Polymorphism Increased the Risk of Hepatocellular Carcinoma Through the miR-3196-Dependent Approach in Chinese Han Population.Pharmacogenomics and personalized medicine · 2021Article
- Molecular signatures of aggressive pediatric liver cancer.Archives of stem cell and therapy · 2021Article
- Application of NRS2002 in Preoperative Nutritional Screening for Patients with Liver Cancer.Journal of oncology · 2021Article
- Cancer stem cells: a major culprit of intra-tumor heterogeneity.American journal of cancer research · 2021Review
- Small Molecule Cjoc42 Improves Chemo-Sensitivity and Increases Levels of Tumor Suppressor Proteins in Hepatoblastoma Cells and in Mice by Inhibiting Oncogene Gankyrin.Frontiers in pharmacology · 2021Article
- Molecular Mechanisms of Hepatoblastoma.Seminars in liver disease · 2021Article
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Authors and funding
8 authors at 2 institutions in 1 country.
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Abstract
Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer.
conclusionThe earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871).
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