Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism.
Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism.
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NDUFB9的下调通过介导线粒体代谢促进乳腺癌细胞增殖和转移
DOI：
10.1371/journal.pone.0144441
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jin W
中科院分区：
文献类型：
--
作者：
Li LD;Sun HF;Liu XX;Gao SP;Jiang HL;Hu X;Jin W
尽管基础和临床研究取得了进展，但转移仍然是乳腺癌患者死亡的主要原因。线粒体的遗传异常，包括影响复合体I和氧化磷酸化的突变，在乳腺癌中被发现，并可能促进转移。编码复合体I组分的基因具有显著的乳腺癌预后价值。在这项研究中，我们使用定量蛋白质组学分析来比较高转移癌细胞系和亲本乳腺癌细胞系；观察到线粒体膜呼吸链NADH脱氢酶（复合体I）的辅助亚基NDUFB9在高转移性乳腺癌细胞中下调。此外，我们证明NDUFB9的缺失会促进MDA-MB-231细胞的增殖、迁移和侵袭，因为mtROS水平升高、NAD+/NADH平衡受到干扰以及mtDNA的耗尽。我们还发现Akt/mTOR/p70S6K信号通路和EMT可能参与了这一机制。因此，我们的研究结果提供了新的数据，支持线粒体复合体I NADH脱氢酶活性的错误调节可以大大增强人乳腺癌细胞的侵袭性的假设，表明复合体I缺乏是一个潜在的重要生物标志物，可用于进一步的基础研究或临床应用。
Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I), was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application.