ArticleJournal of experimental & clinical cancer research : CR2023
TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling.
Article in Journal of experimental & clinical cancer research : CR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Hypoxia and Oxidation Pathway Crosstalk in Head and Neck Squamous Cell Carcinoma.Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · 2026Article
- miR-941 in extracellular vesicles confers anlotinib resistance via Keap1/Nrf2 axis and represents a therapeutic target in non-small cell lung cancer.Clinical and translational medicine · 2026Article
- Platycodin D sensitizes head and neck squamous cell carcinoma to cisplatin by inducing autophagy arrest.Oncology reports · 2026Article
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Apigenin combined with aerobic exercise alleviates oxidative stress and inflammation in high-fat diet-induced NAFLD mice by modulating the Keap1/Nrf2/ARE pathway.Scientific reports · 2026Article
- Cationic nanoparticles-enabled mouthwash combats precancerous oral mucosal inflammation.Regenerative biomaterials · 2026Article
- Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.Frontiers in cell and developmental biology · 2026Review
- Characterization of ANXA1 in chemotherapy resistance of head and neck squamous cell carcinoma: insights from artificial intelligence and integrative bioinformatics analysis.Frontiers in cell and developmental biology · 2026Article
- Determining a Stability Prognostic Panel for 636 Patients With Melanoma Using a Machine Learning Computational Framework.Experimental dermatology · 2025Article
- Mechanisms of Resistance to Chemotherapy in Hypopharyngeal Carcinoma.Biomedicines · 2025Review
- PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- USP14 targets FABP5-mediated ferroptosis to promote proliferation and cisplatin resistance of HNSCC.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Article
- Targeting TNFAIP2 with NIR-II CRISPR-Cas9 nanosystem to overcome cisplatin resistance in laryngeal cancer.NPJ precision oncology · 2025Article
- Development of a prognostic model for chemotherapy response and identification of TNFAIP2 as a target in colorectal cancer.Scientific reports · 2025Article
- 3,3'-((3-Hydroxyphenyl)azanediyl)dipropionic Acid Derivatives as a Promising Scaffold Against Drug-Resistant Pathogens and Chemotherapy-Resistant Cancer.Pathogens (Basel, Switzerland) · 2025Article
- Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment.Cell death discovery · 2025Review
- USP10 stabilizes BAZ1A to drive tumor stemness via an epigenetic mechanism in head and neck squamous cell carcinoma.Cell death & disease · 2025Article
- TNFAIP2 promotes NF-κB signaling mediate lymph node metastasis of oral squamous cell carcinoma by protecting IKKβ from ubiquitin proteasome degradation.Cell communication and signaling : CCS · 2025Article
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Abstract
backgroundDrug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC.
methodsWe performed survival and gene set variation analyses based on HNSCC cohorts and identified the critical role of tumor necrosis factor alpha-induced protein 2 (TNFAIP2) in cisplatin-based chemotherapy resistance. Half-maximal inhibitory concentration (IC50) examination, colony formation assays and flow cytometry assays were conducted to examine the role of TNFAIP2 in vitro, while xenograft models in nude mice and 4-nitroquinoline N-oxide (4NQO)-induced HNSCC models in C57BL/6 mice were adopted to verify the effect of TNFAIP2 in vivo. Gene set enrichment analysis (GSEA) and coimmunoprecipitation coupled with mass spectrometry (Co-IP/MS) were performed to determine the mechanism by which TNFAIP2 promotes cisplatin resistance.
resultsHigh expression of TNFAIP2 is associated with a poor prognosis, cisplatin resistance, and low reactive oxygen species (ROS) levels in HNSCC. Specifically, it protects cancer cells from cisplatin-induced apoptosis by inhibiting ROS-mediated c-JUN N-terminal kinase (JNK) phosphorylation. Mechanistically, the DLG motif contained in TNFAIP2 competes with nuclear factor-erythroid 2-related factor 2 (NRF2) by directly binding to the Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), which prevents NRF2 from undergoing ubiquitin proteasome-mediated degradation. This results in the accumulation of NRF2 and confers cisplatin resistance. Positive correlations between TNFAIP2 protein levels and NRF2 as well as its downstream target genes were validated in HNSCC specimens. Moreover, the small interfering RNA (siRNA) targeting TNFAIP2 significantly enhanced the cisplatin treatment effect in a 4NQO-induced HNSCC mouse model.
conclusionsOur results reveal the antioxidant and cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target in improving the cisplatin treatment effect, particularly for patients with cisplatin resistance.
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