ArticleCancer research2007
Metallothionein expression is suppressed in primary human hepatocellular carcinomas and is mediated through inactivation of CCAAT/enhancer binding protein alpha by phosphatidylinositol 3-kinase signaling cascade.
Article in Cancer research, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
58 citing papers in PubMed, 134 citations in OpenAlex.
- Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma.BMC cancer · 2013Trial
- Research Progress on Copper Metabolism, Cuprotosis, and Their Regulatory Mechanism in Tumor Diagnosis and Treatment.Cancer management and research · 2026Review
- Suppression of pseudogene MT2P1 transcription induced by E2F7 inhibits hepatocellular carcinoma cell proliferation and facilitates apoptosis via preserving its parental gene.Cancer biology & therapy · 2025Article
- A review of C/EBP α: a potential novel target for solid tumor intervention.Journal of translational medicine · 2025Review
- Integrated transcriptomics and proteomics analysis of the impact of iodine‑125 in hepatocellular carcinoma.Molecular medicine reports · 2025Article
- Metallothioneins in the Pathogenesis of Liver Diseases: A Review.International journal of hepatology · 2025Review
- Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?Cell communication and signaling : CCS · 2024Review
- Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells.Biomarker research · 2024Article
- Metallothionein expression in feline injection site fibrosarcomas.BMC veterinary research · 2023Article
- Review
- The Difference in Zinc Concentrations Required for Induction among Metallothionein Isoforms Can Be Explained by the Different MTF1 Affinities to MREs in Its Promoter.International journal of molecular sciences · 2022Article
- The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1.Nature cell biology · 2022Article
- Post-Translational Modifications of p53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy.Frontiers in pharmacology · 2022Review
- Revealing the potential mechanism of Astragalus membranaceus improving prognosis of hepatocellular carcinoma by combining transcriptomics and network pharmacology.BMC complementary medicine and therapies · 2021Article
- Metallic Orthodontic Materials Induce Gene Expression and Protein Synthesis of Metallothioneins.Materials (Basel, Switzerland) · 2021Article
- Ferroptosis: The Silver Lining of Cancer Therapy.Frontiers in cell and developmental biology · 2021Review
- Identification of Key Functional Modules and Immunomodulatory Regulators of Hepatocellular Carcinoma.Journal of immunology research · 2021Article
- Review
- C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition.Nature communications · 2020Article
- MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53.Oncogenesis · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Reactive oxygen species (ROS) resulting from chronic inflammation cause liver injury leading to transformation of regenerating hepatocytes. Metallothioneins (MT), induced at high levels by oxidative stress, are potent scavengers of ROS. Here, we report that the levels of MT-1 and MT-2A are drastically reduced in primary human hepatocellular carcinomas (HCCs) and in diethylnitrosamine-induced liver tumors in mice, which is primarily due to transcriptional repression. Expression of the transcription factor, MTF-1, essential for MT expression, and its target gene Zn-T1 that encodes the zinc transporter-1 was not significantly altered in HCCs. Inhibitors of both phosphatidylinositol 3-kinase (PI3K) and its downstream target AKT increased expression of MT genes in HCC cells but not in liver epithelial cells. Suppression of MT-1 and MT-2A by ectopic expression of the constitutively active PI3K or AKT and their up-regulation by dominant-negative PI3K or AKT mutant confirmed negative regulation of MT expression by PI3K/AKT signaling pathway. Further, treatment of cells with a specific inhibitor of glycogen synthase kinase-3 (GSK-3), a downstream effector of PI3K/AKT, inhibited MT expression specifically in HCC cells. Short interfering RNA-mediated depletion of CCAAT/enhancer binding protein alpha (C/EBPalpha), a target of GSK-3, impeded MT expression, which could not be reversed by PI3K inhibitors. DNA binding activity of C/EBPalpha and its phosphorylation at T222 and T226 by GSK-3 are required for MT expression. MTF-1 and C/EBPalpha act in concert to increase MT-2A expression, which probably explains the high level of MT expression in the liver. This study shows the role of PI3K/AKT signaling pathway and C/EBPalpha in regulation of MT expression in hepatocarcinogenesis.
Indexed as
Identifiers
What OpenQuestion holds
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.