标题: | NF-kappa B-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance |
作者: | Chiu, Ching-Feng Chang, Yi-Wen Kuo, Kuang-Tai Shen, Yu-Shiuan Liu, Chien-Ying Yu, Yang-Hao Cheng, Ching-Chia Lee, Kang-Yun Chen, Feng-Chi Hsu, Min-Kung Kuo, Tsang-Chih Ma, Jui-Ti Su, Jen-Liang 生物科技学系 Department of Biological Science and Technology |
关键字: | EGFR;gefitinib;lung cancer;miR-155;NF-kappa B |
公开日期: | 3-五月-2016 |
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 of FOXO3a and was transcriptionally regulated by NF-kappa B, 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-kappa B/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs. |
URI: | http://dx.doi.org/10.1073/pnas.1522612113 http://hdl.handle.net/11536/133782 |
ISSN: | 0027-8424 |
DOI: | 10.1073/pnas.1522612113 |
期刊: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
Volume: | 113 |
Issue: | 18 |
起始页: | E2526 |
结束页: | E2535 |
显示于类别: | Articles |