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http://ir.nhri.org.tw/handle/3990099045/13317
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| Title: | c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation |
| Authors: | Tang, YC;Hsiao, JR;Jiang, SS;Chang, JY;Chu, PY;Liu, KJ;Fang, HL;Lin, LM;Chen, HH;Huang, YW;Chen, YT;Tsai, FY;Lin, SF;Chuang, YJ;Kuo, CC |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research |
| Abstract: | Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer. |
| Date: | 2021-03-11 |
| Relation: | Theranostics. 2021 Mar 11;11(11):5232-5247. |
| Link to: | http://dx.doi.org/10.7150/thno.53417 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1838-7640&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000629071700010 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85102430596 |
| Appears in Collections: | [郭靜娟] 期刊論文
[張俊彥] 期刊論文
[林素芳] 期刊論文
[劉柯俊] 期刊論文
[江士昇] 期刊論文
[張俊彥] 期刊論文
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| SCP85102430596.pdf | | 3353Kb | Adobe PDF | 396 | View/Open |
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