Breast cancer-associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS-mediated AKT activation
Breast cancer-associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS-mediated AKT activation
复制标题
乳腺癌相关线粒体 DNA 单倍群通过 ROS 介导的 AKT 激活促进肿瘤生长
DOI：
10.1002/ijc.31207
复制
发表时间：
2018-05-01
影响因子：
6.4
通讯作者：
Lyu, Jianxin
中科院分区：
文献类型：
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作者：
Ma, Lin;Fu, Qingzi;Lyu, Jianxin
在过去的十年中，线粒体DNA（mtDNA）单倍型组与乳腺癌的发生有关。然而，其潜在机制尚不清楚。结合一项病例对照研究和一个来自中国南方的乳腺癌妇女的大队列，以及利用转线粒体技术的功能分析，我们证明D5单倍型群与乳腺癌风险增加相关[比值比（OR）=2.789; 95%置信区间（CI）[1.318，5.901]; p=0.007]。此外，线粒体呼吸，线粒体ATP含量和膜电位，骨肉瘤和乳腺癌细胞模型的细胞质杂种（胞质杂种）含有mtDNA D5单倍型组比那些与非D5单倍型组。使用体外和体内致瘤性测定，我们发现与非D5单倍型组的细胞相比，D5单倍型组的细胞更容易发生肿瘤。在机制上，D5单倍型群可以至少部分地通过经由苏氨酸308的磷酸化激活v-AKT鼠胸腺瘤病毒癌基因（AKT）来促进肿瘤发生，这是由D5胞质杂交体中增加的活性氧产生介导的。我们的研究结果表明，与非D5单倍型组的细胞相比，D5单倍型组的细胞线粒体功能降低，这可能与乳腺癌中肿瘤生长增加有关。
In the last decade, mitochondrial DNA (mtDNA) haplogroups have been associated with the occurrence of breast cancer. However, the underlying mechanism is not known. Combining a case-control study with a large cohort of women from Southern China with breast cancer and functional analyses with trans-mitochondrial technology, we demonstrate that the D5 haplogroup is associated with an increased risk of breast cancer [odds ratio (OR)=2.789; 95% confidence interval (CI) [1.318, 5.901]; p=0.007]. Furthermore, mitochondrial respiration, mitochondrial ATP content and membrane potential, were lower in both bone osteosarcoma and breast cancer cell models of cytoplasmic hybrids (cybrids) containing the mtDNA D5 haplogroup than in those with non-D5 haplogroups. Using in vitro and in vivo tumorigenicity assays, we found that cells with the D5 haplogroup were more susceptible to tumorigenesis compared to cells with non-D5 haplogroups. Mechanistically, the D5 haplogroup may promote tumorigenesis at least partially through activation of the v-AKT murine thymoma viral oncogene (AKT) via phosphorylation of threonine 308, which is mediated by increased reactive oxygen species generation in D5 cybrids. Our findings demonstrate that there is decreased mitochondrial function in cells with the D5 haplogroup compared to cells with non-D5 haplogroups, which may be associated with increased neoplastic growth in breast cancer.