Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis.
Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis.
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线粒体裂变通过 BRCA1→miR-593-5p→MFF 轴决定舌鳞状细胞癌的顺铂敏感性
DOI：
10.18632/oncotarget.3659
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发表时间：
2015-06-20
期刊：
影响因子：
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通讯作者：
Li J
中科院分区：
文献类型：
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作者：
Fan S;Liu B;Sun L;Lv XB;Lin Z;Chen W;Chen W;Tang Q;Wang Y;Su Y;Jin S;Zhang D;Zhong J;Li Y;Wen B;Zhang Z;Yang P;Zhou B;Liang Q;Yu X;Zhu Y;Hu P;Chu J;Huang W;Feng Y;Peng H;Huang Q;Song E;Li J
顺铂已被广泛用作多种实体肿瘤的基础化疗药物，增加肿瘤对顺铂的敏感性在过去30年中一直是人们感兴趣的话题。强有力的证据表明，线粒体分裂参与了许多疾病的细胞凋亡调节；然而，线粒体分裂是否调节顺铂的敏感性仍然知之甚少。在此，我们发现MFF介导了顺铂处理后舌鳞状细胞癌(TSCC)细胞的线粒体分裂和凋亡，miR-593-5p在这一过程中下调。MIR-593-5P通过靶向MFF3‘非翻译区序列并抑制其翻译来减弱线粒体分裂和顺铂的敏感性。为了探讨miR-593-5p下调的可能机制，我们在体外观察到BRCA1反式激活miR-593-5p的表达并降低顺铂的敏感性。BRCA1-miR-593-5P-MFF轴在体内也影响顺铂的敏感性。重要的是，在对多个中心的回顾分析中，我们进一步发现BRCA1-miR-593-5p-MFF轴与顺铂敏感性和TSCC患者的生存显著相关。综上所述，我们的数据揭示了线粒体在转录和转录后水平上的分裂调控模型；我们也揭示了BRCA1通过线粒体分裂程序决定顺铂敏感性的新途径。
Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3′ untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.