ArticleJournal of experimental & clinical cancer research : CR2021
HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 109 citations in OpenAlex.
- Neurotransmitter receptor-associated gene signature: prognostic and immunosuppressive microenvironment in NSCLC.Future science OA · 2026Article
- Exosomal circ-ZNF652 Mediates TGF-β1-Induced Epithelial-Mesenchymal Transition and Glycolytic Reprogramming to Promote Hepatocellular Carcinoma Progression.Journal of microbiology and biotechnology · 2026Article
- Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.Redox biology · 2026Review
- Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.Translational lung cancer research · 2026Review
- Recent advances in engineered nanozymes for precision lung cancer therapy.Materials today. Bio · 2026Review
- Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment.Clinical and translational medicine · 2026Review
- Article
- Effects of Tumor Microenvironment on Lung Cancer Stem Cells: Bidirectional Regulatory Mechanisms.Cancer medicine · 2026Review
- Sotatercept Reverses SIN3a Deficiency-Driven PAH by Reprogramming BMPR2/TGF-β-HIF-1α Signaling Pathways.bioRxiv : the preprint server for biology · 2026Article
- Molecular Insights into BZW1 Expression and [Molecular imaging and biology · 2026Article
- Hypoxia-Inducible Factor 1-α in Autoimmune Diseases-Insights from the Paradigm of Hashimoto's Thyroiditis: A Narrative Review.Medical sciences (Basel, Switzerland) · 2026Review
- Targeted metabolism creates possibilities for lung cancer treatment in the precision tumor era.Respiratory research · 2026Review
- The mechanism of PKM2/HIF-1α axis polarizing TAMs by upregulating glucose-serine metabolism to promote melanoma progression.Frontiers in immunology · 2026Article
- Comparative proteomic analysis of colorectal cancer stem cells reveals potential biomarkers and altered pathways.Frontiers in molecular biosciences · 2026Article
- Research Advances in the Endometriotic Microenvironment: Synergistic Immune-Inflammatory-Angiogenic Interactions and their Therapeutic Translation.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Obstructive sleep apnea and lung cancer: molecular underpinnings and clinical translational prospects.Frontiers in cell and developmental biology · 2026Review
- A machine learning-derived hypoxia- and lactylation-associated gene signature for prognostic stratification and immune landscape characterization in lung adenocarcinoma.Frontiers in immunology · 2026Article
- Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis.Clinical and translational medicine · 2025Article
- Role of signaling pathways in lung cancer development and advances in targeted therapies (Review).Oncology letters · 2025Review
- The role and mechanisms of the HIF-1 signaling pathway in LC-COPD.Journal of cancer research and clinical oncology · 2025Review
12 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMost cancer cells have fundamentally different metabolic characteristics, particularly much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer.
methodsWe used the PET/MRI imaging system to observe the glucose metabolism of subcutaneous tumors in nude mice. Energy metabolism of non-small cell lung cancer cell lines detected by the Seahorse XFe96 cell outflow analyzer. Co-immunoprecipitation assays were used to detect the binding of Smads and HIF-1α. Western blotting and qRT-PCR were used to detect the regulatory effects of TGF-β and HIF-1α on c-MYC, PKM1/2, and cell cycle-related genes.
resultsWe discovered that TGF-β could inhibit glycolysis under normoxia while significantly promoting tumor cells' glycolysis under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited p15/p21 and promoted the proliferation of tumor cells under hypoxia.
conclusionsOur results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.
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