國家衛生研究院 NHRI:Item 3990099045/9705
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    题名: NF-kappaB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance
    其它题名: NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance
    作者: Chiu, CF;Chang, YW;Kuo, KT;Shen, YS;Liu, CY;Yu, YH;Cheng, CC;Lee, KY;Chen, FC;Hsu, MK;Kuo, TC;Ma, JT;Su, JL
    贡献者: National Institute of Cancer Research;Division of Biostatistics and Bioinformatics
    摘要: Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR ofFOXO3aand was transcriptionally regulated by NF-kappaB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-kappaB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.
    日期: 2016-04-18
    關聯: Proceedings of the National Academy of Sciences of the United States of America. 2016 Apr 18;113(18):E2526-E2535.
    Link to: http://dx.doi.org/10.1073/pnas.1522612113
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0027-8424&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000375395700010
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84970984338
    显示于类别:[蘇振良] 期刊論文
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