ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis
ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis
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DOI：
10.1126/science.1156906
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发表时间：
2008-05-02
期刊：
影响因子：
56.9
通讯作者：
Hayashi, Jun-Ichi
中科院分区：
文献类型：
--
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
线粒体DNA（mtDNA）突变在人类肿瘤中高频发生，但这些突变是否会改变肿瘤细胞的行为尚不明确。我们利用细胞质杂交（cybrid）技术，将转移性差的小鼠肿瘤细胞系中的内源性mtDNA替换为来自高转移性细胞系的mtDNA，反之亦然。通过对小鼠转移情况的检测，我们发现受体肿瘤细胞获得了所转移mtDNA的转移潜能。赋予高转移潜能的mtDNA在编码NADH（烟酰胺腺嘌呤二核苷酸还原型）脱氢酶亚基6（ND6）的基因中包含G13997A和13885insC突变。这些突变导致呼吸链复合物I活性缺陷，并与活性氧（ROS）的过量产生有关。用ROS清除剂预处理高转移性肿瘤细胞可抑制其在小鼠体内的转移潜能。这些结果表明，mtDNA突变可通过增强肿瘤细胞的转移潜能促进肿瘤进展。
Mutations in mitochondrial DNA ( mtDNA) occur at high frequency in human tumors, but whether these mutations alter tumor cell behavior has been unclear. We used cytoplasmic hybrid ( cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic, and vice versa. Using assays of metastasis in mice, we found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH ( reduced form of nicotinamide adenine dinucleotide) dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species ( ROS). Pretreatment of the highly metastatic tumor cells with ROS scavengers suppressed their metastatic potential in mice. These results indicate that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells.