ArticleOncogene2014
CLIC4 regulates TGF-β-dependent myofibroblast differentiation to produce a cancer stroma.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
What it found
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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.
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.
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Who cites it
45 citing papers in PubMed, 79 citations in OpenAlex.
- Molecular profiling of ex vivo prostate cancer CAF models captures stromal heterogeneity and drug vulnerabilities.Cell death discovery · 2025Article
- Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4).Arthritis research & therapy · 2025Article
- The role of chloride intracellular channel 4 in tumors.Cancer cell international · 2025Review
- Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target.Theranostics · 2025Review
- Article
- Retrograde AAV-mediated gene modulation reveals chloride intracellular channel proteins as potent regulators of retinal ganglion cell death.Experimental neurology · 2024Article
- CLIC4 Function in the Epithelial-Mesenchymal Transition of Epithelial Odontogenic Lesions.Head and neck pathology · 2024Article
- Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on ClInternational journal of molecular sciences · 2023Review
- Crosstalk between tumor and stroma modifies CLIC4 cargo in extracellular vesicles.Journal of extracellular biology · 2023Article
- The stromal immunoexpression of CLIC4 may be related to the difference in the biological behavior between oral squamous cell carcinoma and oral verrucous carcinoma.Medicina oral, patologia oral y cirugia bucal · 2023Article
- Cancer-Associated Fibroblast Heterogeneity and Its Influence on the Extracellular Matrix and the Tumor Microenvironment.International journal of molecular sciences · 2023Review
- Article
- CAFs orchestrates tumor immune microenvironment-A new target in cancer therapy?Frontiers in pharmacology · 2023Review
- Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein.Computational and structural biotechnology journal · 2023Article
- Review
- Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence.PLoS genetics · 2022Article
- Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation.Cells · 2022Article
- Role of the hedgehog signaling pathway in rheumatic diseases: An overview.Frontiers in immunology · 2022Review
- Ion channels as a therapeutic target for renal fibrosis.Frontiers in physiology · 2022Review
- Targeting the extracellular matrix for immunomodulation: applications in drug delivery and cell therapies.Drug delivery and translational research · 2021Review
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 4 institutions in 1 country.
Funding
Abstract
Cancer stroma has a profound influence on tumor development and progression. The conversion of fibroblasts to activated myofibroblasts is a hallmark of reactive tumor stroma. Among a number of factors involved in this conversion, transforming growth factor (TGF)-β has emerged as a major regulator. CLIC4, an integral protein in TGF-β signaling, is highly upregulated in stroma of multiple human cancers, and overexpression of CLIC4 in stromal cells enhances the growth of cancer xenografts. In this study, we show that conditioned media from tumor cell lines induces expression of both CLIC4 and the myofibroblast marker alpha smooth muscle actin (α-SMA) in stromal fibroblasts via TGF-β signaling. Genetic ablation of CLIC4 in primary fibroblasts prevents or reduces constitutive or TGF-β-induced expression of α-SMA and extracellular matrix components that are markers of myofibroblasts. CLIC4 is required for the activation of p38 map kinase by TGF-β, a pathway that signals myofibroblast conversion in stromal cells. This requirement involves the interaction of CLIC4 with PPM1a, the selective phosphatase of activated p38. Conditioned media from fibroblasts overexpressing CLIC4 increases tumor cell migration and invasion in a TGF-β-dependent manner and promotes epithelial to mesenchymal transition indicating that high stromal CLIC4 serves to enhance tumor invasiveness and progression. Thus, CLIC4 is significantly involved in the development of a nurturing tumor microenvironment by enhancing TGF-β signaling in a positive feedback loop. Targeting CLIC4 in tumor stroma should be considered as a strategy to mitigate some of the tumor enhancing effects of the cancer stroma.
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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.