ArticleOncogene2017
Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 2 of them syntheses that pooled it.
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Who cites it
77 citing papers in PubMed, 2 syntheses or guidelines pooled it, 116 citations in OpenAlex.
- The relationship between aspirin consumption and hepatocellular carcinoma: a systematic review and meta-analysis.European journal of medical research · 2023Pooled it
- Aspirin for the prevention of hepatocellular carcinoma: an updated meta-analysis with particular focus on patients with chronic liver disease.European journal of clinical pharmacology · 2022Pooled it
- Trial
- Mitochondria-mediated anticancer effects of two previously characterized COX-2 inhibitors in hepatocellular carcinoma.Molecular and cellular biochemistry · 2026Article
- Celecoxib inhibits COX-2 and initiates YAP-dependent mitochondrial apoptosis via YBX1 shuttling in hepatocellular carcinoma.Cell communication and signaling : CCS · 2026Article
- ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.Cell reports · 2026Article
- Review
- Article
- Aspirin reduces short-term mortality risk in critically ill patients with liver cirrhosis: a propensity-score matched retrospective analysis using the MIMIC-IV database.BMC gastroenterology · 2025Article
- Chemoprevention of hepatocellular carcinoma.Hepatology communications · 2025Review
- TET1: The epigenetic architect of clinical disease progression.Genes & diseases · 2025Review
- Pharmacological Treatment of MASLD: Contemporary Treatment and Future Perspectives.International journal of molecular sciences · 2025Review
- Ten-Eleven Translocation Family Proteins: Structure, Biological Functions, Diseases, and Targeted Therapy.MedComm · 2025Review
- DNA Methyltransferases 1-Regulated Methylation of Protein Kinase C Zeta Influences Its Expression in Breast Cancer Cells.Journal of breast cancer · 2025Article
- PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis.JHEP reports : innovation in hepatology · 2025Article
- Mechanisms ofAmerican journal of translational research · 2025Article
- Evaluating the Role of Aspirin in Liver Disease: Efficacy, Safety, Potential Benefits and Risks.Life (Basel, Switzerland) · 2024Review
- Gut microbiota of miR-30a-5p-deleted mice aggravate high-fat diet-induced hepatic steatosis by regulating arachidonic acid metabolic pathway.Clinical and translational medicine · 2024Article
- Inhibition of NF-kB and COX-2 by andrographolide regulates the progression of cervical cancer by promoting PTEN expression and suppressing PI3K/AKT signalling pathway.Scientific reports · 2024Article
- Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors.NAR cancer · 2024Article
17 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX-2 represents a mechanism-based target for HCC prevention.
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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.