Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis
Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis
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DOI：
10.1158/0008-5472.can-04-2012
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发表时间：
2005-03-01
期刊：
影响因子：
11.2
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Shidara, Y;Yamagata, K;Ohta, S
线粒体功能障碍在癌症中的作用一直是人们极大兴趣和正在进行的研究的主题。尽管大多数癌细胞在线粒体 DNA (mtDNA) 中存在体细胞突变，但此类突变是否会促进癌症的发生这一问题仍未得到解决。在这里，我们使用包含共同 HeLa 核和感兴趣的 mtDNA 的跨线粒体杂交体（cybrids）来比较 mtDNA 与共同核背景的作用。我们在源自线粒体脑肌病患者的 mtDNA ATP 合酶亚基 6 基因 (MTATP6) 的核苷酸位置 8,993 或 9,176 处构建了具有或不具有同质致病点突变的细胞杂种。当将cybrids移植到裸鼠体内时，MTATP6突变在肿瘤生长的早期阶段赋予了优势。突变体胞质杂种在培养中也比野生型增加得更快。为了补充 mtDNA 突变，我们将 MTATP 的野生型核版本转染到携带突变 MTATP6 的细胞核中，其密码子被转换为包含线粒体靶序列的通用遗传密码。 MTATP的恢复减缓了移植中肿瘤的生长。相反，野生型细胞杂种中 MTATP6 突变核的表达降低了呼吸作用并加速了肿瘤生长。这些发现表明，肿瘤生长的优势取决于 MTATP6 功能，而不是由于突变线粒体引起的二次核突变。由于与野生型细胞杂种相比，在培养物和肿瘤中突变体细胞凋亡发生的频率较低，因此致病性 mtDNA 突变似乎通过阻止细胞凋亡来促进肿瘤。
The role of mitochondrial dysfunction in cancer has been a subject of great interest and much ongoing investigation. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations contribute to the promotion of carcinomas remains unsolved. Here we used trans-mitochondrial hybrids (cybrids) containing a common HeLa nucleus and mtDNA of interest to compare the role of mtDNA against the common nuclear background. We constructed cybrids with or without a homoplasmic pathogenic point mutation at nucleotide position 8,993 or 9,176 in the mtDNA ATP synthase subunit 6 gene (MTATP6) derived from patients with mitochondrial encephalomyopathy. When the cybrids were transplanted into nude mice, the MTATP6 mutations conferred an advantage in the early stage of tumor growth. The mutant cybrids also increased faster than wild type in culture. To complement the mtDNA mutations, we transfected a wild-type nuclear version of MTATP, whose codons were converted to the universal genetic codes containing a mitochondrial target sequence, into the nucleus of cybrids carrying mutant MTATP6. The restoration of MTATP slowed down the growth of tumor in transplantation. Conversely, expression of a mutant nuclear version of MTATP6 in the wild-type cybrids declined respiration and accelerated the tumor growth. These findings showed that the advantage in tumor growth depended upon the MTATP6 function but was not due to secondary nuclear mutations caused by the mutant mitochondria. Because apoptosis occurred less frequently in the mutant versus wild-type cybrids in cultures and tumors, the pathogenic mtDNA mutations seem to promote tumors by preventing apoptosis.