Academic Journal
TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling
| العنوان: | TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling |
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| المؤلفون: | Xu, Teng, Yang, Yuemei, Chen, Zhihong, Wang, Jinsong, Wang, Xiaolei, Zheng, Yang, Wang, Chao, Wang, Yachen, Zhu, Zaiou, Ding, Xu, Zhou, Junbo, Li, Gang, Zhang, Hongchuang, Zhang, Wei, Wu, Yunong, Song, Xiaomeng |
| المساهمون: | National Natural Science Foundation of China, Jiangsu Provincial Medical Innovation Team |
| المصدر: | Journal of Experimental & Clinical Cancer Research ; volume 42, issue 1 ; ISSN 1756-9966 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | Background Drug 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. Methods We 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. Results High 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. Conclusions Our results reveal the antioxidant and cisplatin ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1186/s13046-023-02775-1 |
| DOI: | 10.1186/s13046-023-02775-1.pdf |
| DOI: | 10.1186/s13046-023-02775-1/fulltext.html |
| الاتاحة: | http://dx.doi.org/10.1186/s13046-023-02775-1 https://link.springer.com/content/pdf/10.1186/s13046-023-02775-1.pdf https://link.springer.com/article/10.1186/s13046-023-02775-1/fulltext.html |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.8C9C098 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s13046-023-02775-1 |
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