ArticleCancer research2022
Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non-Cell Autonomous Liver Carcinogenesis.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectives on malignant progression.Journal of gastroenterology · 2026Review
- Dual-stress-responsive-pathways prevent HCC initiation via p53 suppression of MTHFD1L-RNA mResearch square · 2026Article
- Therapy-induced senescent cancer cells as bidirectional regulators of antitumor immunity and resistance in the tumor microenvironment.Cell death & disease · 2026Review
- KRAB Zinc-Finger Protein ZNF205 Promotes Hepatocellular Carcinoma via p53 Pathway Repression.Cancer science · 2026Article
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- Multimodal clinical parameters-based immune status associated with the prognosis in patients with hepatocellular carcinoma.World journal of gastrointestinal oncology · 2026Review
- Integrating single cell- and spatial- resolved transcriptomics unravels the inter-tumor heterogeneity and immunosuppressive landscape in HBV- and Clonorchis sinensis-associated hepatocellular carcinoma.Molecular cancer · 2026Article
- Identification of high-risk signatures and therapeutic targets through molecular characterization and immune profiling of TP53-mutant breast cancer.Journal, genetic engineering & biotechnology · 2025Article
- RELA Ablation Contributes to Progression of Hepatocellular Carcinoma with TP53Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- UBE2S inhibits colorectal cancer proliferation by regulating the PI3K/AKT and MAPK/ERK pathways via TRAF6.Scientific reports · 2025Article
- RNF4 and USP7 coordinate spatial regulation of SLX4 stability within the PML nuclear bodies.Nucleic acids research · 2025Article
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- Persistent accumulation of therapy-induced senescent cells: an obstacle to long-term cancer treatment efficacy.International journal of oral science · 2025Review
- The key target and role of betel nut in oral squamous cell carcinoma.BMC oral health · 2025Article
- Targeting inflammation in cancer therapy: from mechanistic insights to emerging therapeutic approaches.Journal of translational medicine · 2025Review
- Assessing phototoxic drug properties of hydrochlorothiazide using human skin biopsies.Communications biology · 2025Article
- High-Frequency Mutations in TP53, AXIN1, CTNNB1, and KRAS, and Polymorphisms in JAK1 Genes Among Mongolian HCC Patients.Cancer reports (Hoboken, N.J.) · 2025Article
- Cellular senescence offers distinct immunological vulnerabilities in cancer.Trends in cancer · 2025Review
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13 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
In chronic liver diseases (CLD), p53 is constitutively activated in hepatocytes due to various etiologies as viral infection, ethanol exposure, or lipid accumulation. This study was aimed to clarify the significance of p53 activation on the pathophysiology of CLDs. In Kras-mutant liver cancer model, murine double minute 2 (Mdm2), a negative regulator of p53, was specifically deleted in hepatocytes [Alb-Cre KrasLSL-G12D Mdm2fl/fl (LiKM; KrasG12D mutation and Mdm2 loss in the liver)]. Accumulation of p53 and upregulation of its downstream genes were observed in hepatocytes in LiKM mice. LiKM mice showed liver inflammation accompanied by hepatocyte apoptosis, senescence-associated secretory phenotype (SASP), and the emergence of hepatic progenitor cells (HPC). More importantly, Mdm2 deletion promoted non-cell autonomous development of liver tumors. Organoids generated from HPCs harbored tumor-formation ability when subcutaneously inoculated into NOD/Shi-scid/IL2Rγ (null) mice. Treatment with acyclic retinoid suppressed growth of HPCs in vitro and inhibited tumorigenesis in LiKM mice. All of the phenotypes in LiKM mice, including accelerated liver tumorigenesis, were negated by further deletion of p53 in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl p53fl/fl). Activation of hepatic p53 was noted in liver biopsy samples obtained from 182 patients with CLD, in comparison with 23 normal liver samples without background liver diseases. In patients with CLD, activity of hepatic p53 was positively correlated with the expression of apoptosis, SASP, HPC-associated genes and tumor incidence in the liver after biopsy. In conclusion, activation of hepatocyte p53 creates a microenvironment prone to tumor formation from HPCs. Optimization of p53 activity in hepatocytes is important to prevent patients with CLD from hepatocarcinogenesis. SIGNIFICANCE: This study reveals that activation of p53 in hepatocytes promotes liver carcinogenesis derived from HPCs, which elucidates a paradoxical aspect of a tumor suppressor p53 and novel mechanism of liver carcinogenesis. See related commentary by Barton and Lozano, p. 2824.
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