Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer（NSCLC）.Unfortunately,most NSCLC patients inevitably develop gefitinib resistance during treatment.In addition to EGFR mutation stat...Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer（NSCLC）.Unfortunately,most NSCLC patients inevitably develop gefitinib resistance during treatment.In addition to EGFR mutation status,the mechanisms involved are largely unknown.In this study,we showed that mi R-124,a tumor suppressor,was significantly down-regulated in gefitinib-resistant NSCLC patients and cell lines compared with gefitinib-sensitive patients and cell lines.In addition,the mi R-124 depletion induced gefitinib resistance,and mi R-124 overexpression sensitized gefitinib-resistant cells to gefitinib.Mechanistic analysis revealed that mi R-124 decreased SNAI2 and STAT3 expression by directly targeting their 3＇UTRs and that knocking down SNAI2 or STAT3 partly reversed the gefitinib resistance induced by mi R-124 depletion.Our data demonstrate that the mi R-124 plays a new critical role in acquired resistance to gefitinib and that the manipulation of mi R-124 might provide a therapeutic strategy for reversing acquired gefitinib resistance.展开更多
基金supported by the grants from National Natural Science Foundation of China(No.81301899 and 81372662)Wu Jie Ping Medical Foundation(No.320.6750.1239)the Special Funds for Major State Basic Research Program of China(973 Program)(No.2009CB521802)
文摘Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer（NSCLC）.Unfortunately,most NSCLC patients inevitably develop gefitinib resistance during treatment.In addition to EGFR mutation status,the mechanisms involved are largely unknown.In this study,we showed that mi R-124,a tumor suppressor,was significantly down-regulated in gefitinib-resistant NSCLC patients and cell lines compared with gefitinib-sensitive patients and cell lines.In addition,the mi R-124 depletion induced gefitinib resistance,and mi R-124 overexpression sensitized gefitinib-resistant cells to gefitinib.Mechanistic analysis revealed that mi R-124 decreased SNAI2 and STAT3 expression by directly targeting their 3＇UTRs and that knocking down SNAI2 or STAT3 partly reversed the gefitinib resistance induced by mi R-124 depletion.Our data demonstrate that the mi R-124 plays a new critical role in acquired resistance to gefitinib and that the manipulation of mi R-124 might provide a therapeutic strategy for reversing acquired gefitinib resistance.
