ArticleHepatology (Baltimore, Md.)2015
Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 128 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
128 citing papers in PubMed, 1 synthesis or guideline pooled it, 192 citations in OpenAlex.
- Narrow-margin hepatectomy combined with external beam radiotherapy in patients with hepatocellular carcinoma: a systematic review and meta-analysis.BMC cancer · 2025Pooled it
- A Randomized Controlled Pilot Study Evaluating the Safety and Efficacy of Nifuroxazide in Patients with Ulcerative Colitis.Drug design, development and therapy · 2025Trial
- A positive feedback loop between Periostin and TGFβ1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.Journal of experimental & clinical cancer research : CR · 2021Trial
- Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial.Oncoimmunology · 2020Trial
- HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis.The Journal of clinical investigation · 2018Trial
- Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.Journal of hematology & oncology · 2026Review
- A Review of Recent Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hepatocellular Carcinoma.Medical science monitor : international medical journal of experimental and clinical research · 2026Review
- Understanding how hypoxia contributes to liver cancer stem cells maintenance.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators.Cells · 2026Review
- Functional Role of COP1 Gene in Hepatocellular Carcinoma Lipid Metabolism and Stemness.Genes to cells : devoted to molecular & cellular mechanisms · 2026Article
- Macrophage-delivered Nifuroxazide reprograms immunosuppressive microenvironment and synergizes with oxaliplatin for enhanced anti-hepatocellular carcinoma therapy.Journal of nanobiotechnology · 2026Article
- Sorafenib nanomedicine in HCC: nano-bio interactions and combination therapies.Journal of nanobiotechnology · 2026Review
- Beyond molecular classification: integrating signaling, subcellular, and immune reprogramming in endometrial cancer.Frontiers in oncology · 2026Review
- Research Progress on the Molecular Mechanism of Metformin Regulating AMPK Signaling Pathway in Inhibiting Liver Cancer.OncoTargets and therapy · 2026Review
- Uncovering key markers and therapeutic targets for renal fibrosis in diabetic kidney disease through bulk and single-cell RNA sequencing.Journal of translational medicine · 2025Article
- LncRNAs in hypoxic microenvironment; insight in their impact in cancer biology.Functional & integrative genomics · 2025Review
- ECT2NPJ precision oncology · 2025Article
- Prominosomes - a particular class of extracellular vesicles containing prominin-1/CD133?Journal of nanobiotechnology · 2025Review
- Nanocomposites to Overcoming Sorafenib Resistance in Hepatocellular Carcinoma Therapy.International journal of nanomedicine · 2025Review
- Unveiling the impact of CD133 on cell cycle regulation in radio- and chemo-resistance of cancer stem cells.Frontiers in public health · 2025Review
68 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
unlabelledEnhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins.
conclusionIL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.
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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.