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
目的:探讨N-乙酰基-丝氨酰-天门冬酰-赖氨酰-脯氨酸(Ac-SDKP)是否通过抑制热休克蛋白27(heat-shock protein 27,HSP 27)的表达,进而抑制锌指蛋白SNAI1、SNAI2的表达,而发挥阻抑转化生长因子(TGF)-β1诱导的人肺泡Ⅱ型上皮细胞向间质细胞...目的:探讨N-乙酰基-丝氨酰-天门冬酰-赖氨酰-脯氨酸(Ac-SDKP)是否通过抑制热休克蛋白27(heat-shock protein 27,HSP 27)的表达,进而抑制锌指蛋白SNAI1、SNAI2的表达,而发挥阻抑转化生长因子(TGF)-β1诱导的人肺泡Ⅱ型上皮细胞向间质细胞(肌成纤维细胞)的转化以及Ⅰ型、Ⅲ型胶原蛋白的表达。方法:激光共聚焦检测TGF-β1诱导的人肺泡Ⅱ型上皮细胞向肌成纤维细胞转化中HSP27及SNAI1、SNAI2蛋白的共定位表达;real-time PCR法检测HSP27、SNAI1和SNAI2 mRNA的表达;Western blotting法检测HSP27、SNAI1、SNAI2和Ⅰ型、Ⅲ型胶原蛋白的表达,以及转染HSP27干扰质粒后SNAI1、SNAI2蛋白及Ⅰ型、Ⅲ型胶原蛋白表达的变化。结果:与对照组相比,TGF-β1刺激组HSP27、SNAI1、SNAI2及Ⅰ型、Ⅲ型胶原蛋白表达增强;给予Ac-SDKP干预后,HSP27、SNAI1、SNAI2及Ⅰ型、Ⅲ型胶原蛋白表达明显降低,差异有统计学意义。用HSP27的干扰质粒转扰细胞后,SNAI1、SNAI2及Ⅰ型、Ⅲ型胶原蛋白表达降低,其中SNAI1和Ⅰ型、Ⅲ型胶原蛋白的表达与TGF-β1刺激组比较差异有统计学意义。这与Ac-SDKP干预的结果相似。结论:Ac-SDKP能够通过对HSP27表达的调节,降低锌指蛋白SNAI1和SNAI2的表达,进而抑制肺泡Ⅱ型上皮细胞向肌成纤维细胞的转化及胶原蛋白的合成。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.
