mtDNA mutations increase tumorigenicity in prostate cancer
mtDNA mutations increase tumorigenicity in prostate cancer
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DOI：
10.1073/pnas.0408894102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Wallace, DC
中科院分区：
文献类型：
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作者：
Petros, JA;Baumann, AK;Wallace, DC
线粒体 DNA 突变已被发现满足引起前列腺癌的致病性突变的所有预期标准。关注细胞色素氧化酶亚基 I (COI) 基因，我们发现 11-12% 的前列腺癌患者携带 COI 突变，改变保守氨基酸（平均保守指数 = 83%），而 < 2% 的非癌症对照和 7.8% 的普通人群有 COI 突变，后者改变不太保守的氨基酸（保守指数 = 71%）。在不同 mtDNA 背景的多个独立患者中发现了四种保守的前列腺癌 COI 突变。另外三种肿瘤含有异质 COI 突变，其中一种产生了终止密码子。后一种肿瘤还含有种系 ATP6 突变。因此，种系和体细胞 mtDNA 突变都会导致前列腺癌。已发现许多肿瘤会产生更多的活性氧 (ROS)，而抑制氧化磷酸化的 mtDNA 突变会增加 ROS 的产生，从而导致致瘤性。为了确定突变肿瘤是否增加了 ROS 和肿瘤生长速率，我们通过细胞杂交将致病性 mtDNA ATP6 T8993G 突变引入 PO 前列腺癌细胞系，并在裸鼠中测试肿瘤生长。发现所产生的突变体（T8993G）细胞杂种产生的肿瘤比野生型（T8993T）细胞杂种大7倍，而野生型细胞杂种在小鼠体内几乎不生长。突变肿瘤还产生显着更多的ROS。因此，mtDNA突变确实在前列腺癌的病因学中发挥着重要作用。
Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11-12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation index = 83%),whereas < 2% of no-cancer controls and 7.8% of the general population had COI mutations, the latter altering less conserved amino acids (conservation index = 71%). Four conserved prostate cancer COI mutations were found in multiple independent patients on different mtDNA backgrounds. Three other tumors contained heteroplasmic COI mutations, one of which created a stop codon. This latter tumor also contained a germ-line ATP6 mutation. Thus, both germ-line and somatic mtDNA mutations contribute to prostate cancer. Many tumors have been found to produce increased reactive oxygen species (ROS), and mtDNA mutations that inhibit oxidative phosphorylation can increase ROS production and thus contribute to tumorigenicity. To determine whether mutant tumors had increased ROS and tumor growth rates, we introduced the pathogenic mtDNA ATP6 T8993G mutation into the PO prostate cancer cell line through cybrid transfer and tested for tumor growth in nude mice. The resulting mutant (T8993G) cybrids were found to generate tumors that were 7 times larger than the wild-type (T8993T) cybrids, whereas the wild-type cybrids barely grew in the mice. The mutant tumors also generated significantly more ROS. Therefore, mtDNA mutations do play an important role in the etiology of prostate cancer.