ArticleHepatology (Baltimore, Md.)2012
Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss.
Article in Hepatology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Association between TGF-β1 polymorphisms and hepatocellular carcinoma risk: a meta-analysis.Genetic testing and molecular biomarkers · 2013Pooled it
- MicroRNA Control of Hepatocyte-Stromal Crosstalk in the Early Premalignant Microenvironment of HBV-Associated HCC.International journal of molecular sciences · 2026Review
- The p53 Isoforms as Potential Biomarkers in Different Cancer Entities.International journal of molecular sciences · 2026Review
- Effects of the Polar Fraction ofInternational journal of molecular sciences · 2025Article
- Sex-Dependent Regulation of Liver Fibrosis in Primary Sclerosing Cholangitis: The Role of miR-125b, Androgen Receptors, TGF-β, and Apelin Signalling.International journal of molecular sciences · 2025Article
- LncRNA PVT1 activated by TGF-β1/Smad3 facilitates proliferation and metastasis of hepatocellular carcinoma via upregulating Smad6 and NRG1.Journal of translational medicine · 2025Article
- Signaling pathways and therapeutic interventions in gastric cancer.Signal transduction and targeted therapy · 2022Review
- Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.Frontiers in immunology · 2022Article
- The role of p53 in liver fibrosis.Frontiers in pharmacology · 2022Review
- Ameliorative effects of colostrum against DMBA hepatotoxicity in rats.Saudi journal of biological sciences · 2021Article
- LncRNA MIR4435-2HG potentiates the proliferation and invasion of glioblastoma cells via modulating miR-1224-5p/TGFBR2 axis.Journal of cellular and molecular medicine · 2020Article
- Review
- A Transforming Growth Factor-β and H19 Signaling Axis in Tumor-Initiating Hepatocytes That Regulates Hepatic Carcinogenesis.Hepatology (Baltimore, Md.) · 2019Article
- POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1.EBioMedicine · 2019Article
- High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway.International journal of molecular sciences · 2019Review
- Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-β Pathway.Gastroenterology · 2018Article
- Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma.Molecular oncology · 2018Article
- Article
- The TGF-β pathway: a pharmacological target in hepatocellular carcinoma?Hepatic oncology · 2017Article
- Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
unlabelledHepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of TP53 and inhibition of transforming growth factor-beta (TGF-β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF-β signaling, by deletion of the TGF-β receptor, type II (Tgfbr2), cooperates with Trp53 loss to drive HCC formation. Albumin-cre transgenic mice were crossed with floxed Trp53 and/or floxed Tgfbr2 mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of Trp53 alone (Trp53(KO) ) resulted in liver tumors in approximately 41% of mice by 10 months of age, whereas inactivation of Tgfbr2 alone (Tgfbr2(KO) ) did not induce liver tumors. Surprisingly, deletion of Tgfbr2 in the setting of p53 loss (Trp53(KO) ;Tgfbr2(KO) ) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly, Trp53(KO) and Trp53(KO) ;Tgfbr2(KO) mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF-β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF-β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of Trp53(KO) tumors that express increased levels of alpha-fetoprotein. Furthermore, tumors from Trp53(KO) mice express increased TGF-β1 levels compared with tumors from Trp53(KO) ;Tgfbr2(KO) mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from Trp53(KO) mice and correlated with increased expression of the TGF-β responsive genes, Pai1 and Ctgf.
conclusionTGF-β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.