ArticleNeoplasia (New York, N.Y.)2016
A Positive TGF-β/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.
Article in Neoplasia (New York, N.Y.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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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.
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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
22 citing papers in PubMed, 32 citations in OpenAlex.
- Puerarin Reverses UV-Induced Epigenetic Silencing of the Wnt/β-Catenin-KIT Axis to Mitigate Skin Fibroblast Aging.International journal of molecular sciences · 2026Article
- Hepatocellular carcinoma: signaling pathways and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Signaling pathways in liver cancer: pathogenesis and targeted therapy.Molecular biomedicine · 2024Review
- The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats.International journal of molecular sciences · 2024Article
- Oct4 promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in colon cancer cells by activating the SCF/c-Kit signaling pathway.Cell cycle (Georgetown, Tex.) · 2023Article
- Direct and indirect effects of IFN-α2b in malignancy treatment: not only an archer but also an arrow.Biomarker research · 2022Review
- SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways.International journal of molecular sciences · 2021Article
- Dermal Extracellular Matrix-Derived Hydrogels as anTissue engineering. Part A · 2021Article
- C-Kit, a Double-Edged Sword in Liver Regeneration and Diseases.Frontiers in genetics · 2021Review
- A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer.Frontiers in cell and developmental biology · 2021Article
- Skin wound closure delay in metabolic syndrome correlates with SCF deficiency in keratinocytes.Scientific reports · 2020Article
- Review
- Value of ultrasound combined with MRI in the diagnosis of primary and recurrent hepatocellular carcinoma.Oncology letters · 2019Article
- Review
- Mesenchyme-specific deletion of Tgf-β1 in the embryonic lung disrupts branching morphogenesis and induces lung hypoplasia.Laboratory investigation; a journal of technical methods and pathology · 2019Article
- MicroRNA-422a functions as a tumor suppressor in non-small cell lung cancer through SULF2-mediated TGF-β/SMAD signaling pathway.Cell cycle (Georgetown, Tex.) · 2019Article
- Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions.International journal of molecular sciences · 2018Review
- Mesenchymal stem cells prolong the survival of orthotopic liver transplants by regulating the expression of TGF-β1.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2018Article
- Suppression of tumor cell proliferation and migration by human umbilical cord mesenchymal stem cells: A possible role for apoptosis and Wnt signaling.Oncology letters · 2018Article
- Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.Journal of Cancer · 2018Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
unlabelledHepatocellular carcinoma (HCC) is globally the second most common cause of cancer mortality. The majority of HCC patients are diagnosed at advanced stage disease for which no curative treatments exist. TGF-β has been identified as a potential therapeutic target. However, the molecular mechanisms mediating its functional switch from a tumor suppressor to tumor promoter in HCC and its interactions with other signaling pathways are poorly understood. Here, we demonstrate an aberrant molecular network between the TGF-β and c-KIT pathway that mediates the functional switch of TGF-β to a driver of tumor progression in HCC. TGF-β/SMAD2 signaling transcriptionally regulates expression of the c-KIT receptor ligand (stem cell factor [SCF]) with subsequent auto- and paracrine activation of c-KIT/JAK1/STAT3 signaling. SCF induces TGF-β1 ligand expression via STAT3, thereby forming a positive feedback loop between TGF-β/SMAD and SCF/c-KIT signaling. This network neutralizes TGF-β-mediated cell cycle inhibition and induces tumor cell proliferation, epithelial-to-mesenchymal-transition, migration, and invasion. Disruption of this feedback loop inhibits TGF-β tumor-promoting effects and restores its antiproliferative functions. Consistent with our in vitro data, we demonstrate SCF overexpression and its correlation to SMAD2 and STAT3 activation in human HCC tumors, advanced tumor-node-metastasis stages, and shorter survival.
conclusionsCanonical TGF-β and c-KIT signaling forms a positive, tumor-promoting feedback loop. Disruption of this loop restores TGF-β tumor suppressor function and provides the rationale for targeting the TGF-β/SCF axis as a novel therapeutic strategy for HCC.
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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.