ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 2 of them syntheses that pooled it.
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Who cites it
20 citing papers in PubMed, 2 syntheses or guidelines pooled it, 32 citations in OpenAlex.
- Pooled it
- The Prognostic Value of Decreased KLF4 in Digestive System Cancers: A Meta-Analysis from 17 Studies.Disease markers · 2017Pooled it
- TGF-β1/SMAD signaling downregulates KLF4 expression via direct transcriptional suppression and FAT10-mediated proteasomal degradation in hepatocellular carcinoma.Cell & bioscience · 2026Article
- Assessment of peripheral gene expression signatures as predictive biomarkers for hepatocellular carcinoma following DAA treatment.Journal, genetic engineering & biotechnology · 2025Article
- Role of HNF6 in liver homeostasis and pathophysiology.Molecular medicine (Cambridge, Mass.) · 2025Review
- Immunomodulatory role of vitamin D and emerging immunotherapies in hepatocellular carcinoma.Frontiers in nutrition · 2025Review
- KLF4 loss in hepatocellular carcinoma: Improving prognostic prediction and correlating immune infiltrates.Frontiers in genetics · 2023Article
- USP11 degrades KLF4 via its deubiquitinase activity in liver diseases.Journal of cellular and molecular medicine · 2021Article
- Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment.Frontiers in oncology · 2021Review
- Article
- Tuning up Transcription Factors for Therapy.Molecules (Basel, Switzerland) · 2020Review
- Dedifferentiation of hepatocellular carcinoma: molecular mechanisms and therapeutic implications.American journal of translational research · 2020Review
- Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation.World journal of gastroenterology · 2019Article
- Aberrant lipid metabolism as a therapeutic target in liver cancer.Expert opinion on therapeutic targets · 2019Review
- Mechano-signalling, induced by fullerene CInternational journal of nanomedicine · 2019Article
- KLF4-Mediated CDH3 Upregulation Suppresses Human Hepatoma Cell Growth and Migration via GSK-3β Signaling.International journal of biological sciences · 2019Article
- Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET.Oncotarget · 2018Article
- SP and KLF Transcription Factors in Digestive Physiology and Diseases.Gastroenterology · 2017Review
- RYBP Expression Is Regulated by KLF4 and Sp1 and Is Related to Hepatocellular Carcinoma Prognosis.The Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
purposeTumor differentiation is a behavioral index for hepatocellular carcinoma (HCC) and a prognostic factor for patients with HCC who undergo orthotopic liver transplantation (OLT). However, the molecular basis for HCC differentiation and prognostic value of the underlying molecules that regulate HCC differentiation are unclear. In this study, we defined a potential driver pathway for HCC differentiation and prognostication. EXPERIMENTAL
designThe regulation and function of Krüppel-like factor 4 (KLF4) and hepatocyte nuclear factor-6 (HNF-6) in HCC differentiation was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival.
resultsThere was a direct relationship between the expression levels of KLF4 and HNF6 in HCC. Reduced KLF4 or HNF6 expression correlated with high HCC grade. Poorly differentiated HCC cells had lower expression of KLF4 or HNF6 and differentiation-associated markers than did well-differentiated cells. Elevated KLF4 of HNF6 expression induced differentiation of poorly differentiated hepatoma cells. Mechanistically, KLF4 trans-activated HNF-6 expression. Restored HNF-6 expression upregulated expression of differentiation-associated markers and inhibited HCC cell migration and invasion, whereas HNF-6 knockdown did the opposite. Loss of KLF4 expression in primary HCC correlated with reduced overall survival and shortened relapse-free survival durations after OLT. Combination of KLF4 expression and the Milan criteria improved prognostication for HCC after OLT.
conclusionsThe dysregulated KLF4/HNF-6 pathway drives dedifferentition and progression of HCC, and KLF4 is a biomarker for accurate prognostication of patients with HCC treated by OLT when integrated with the Milan Criteria.
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