Decreased mitochondrial DNA mutagenesis in human colorectal cancer.
Decreased mitochondrial DNA mutagenesis in human colorectal cancer.
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DOI：
10.1371/journal.pgen.1002689
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Bielas JH
中科院分区：
文献类型：
--
作者：
Ericson NG;Kulawiec M;Vermulst M;Sheahan K;O'Sullivan J;Salk JJ;Bielas JH
基因组不稳定被认为是癌症的标志。人类肿瘤的线粒体 DNA (mtDNA) 中经常携带克隆扩展突变，其中一些突变可能会导致癌症进展和转移。肿瘤线粒体DNA克隆突变的高发生率通常导致人们假设癌症中的线粒体基因组在遗传上不稳定，但这一假设尚未经过实验检验。在这项研究中，我们直接测量了人类结直肠癌 mtDNA 中非克隆（随机）从头单碱基替换的频率。值得注意的是，相对于邻近的非肿瘤组织，肿瘤组织表现出这些突变的发生率降低。突变负担的差异归因于 C:G 到 T:A 转变的减少，这与氧化损伤有关。我们证明，与非肿瘤性结肠相比，肿瘤组织中较低的随机突变频率还与葡萄糖代谢从氧化磷酸化向无氧糖酵解的转变有关。这些发现共同提出了一个有趣的可能性，即癌症中线粒体基因组的保真度实际上是由于活性氧介导的 mtDNA 损伤减少而增加的。线粒体是负责真核细胞能量产生的细胞内细胞器。它们的独特之处在于它们含有自己的DNA（mtDNA），它编码对线粒体功能很重要的基因，并且是细胞储存在细胞核外的唯一遗传物质。人们认为核和线粒体 DNA 的突变在肿瘤生长和转移中发挥作用。虽然众所周知，核 DNA 会增加人类癌症的总体突变负担，但尚未在线粒体 DNA 中对此进行研究。在这里，我们使用高度灵敏的检测来确定从患者匹配的正常和癌性结肠组织中分离出的 mtDNA 中的突变负荷。令人惊讶的是，我们发现肿瘤中 mtDNA 突变的频率实际上相对于健康组织有所降低，这表明与核 DNA 不同，mtDNA 的加速突变不会促进癌症的发展，甚至可能阻碍癌症的发展。这些发现提出了一种可能性，即专注于直接增加 mtDNA 损伤和突变的线粒体靶向癌症疗法可能会有效抑制恶性生长。
Genome instability is regarded as a hallmark of cancer. Human tumors frequently carry clonally expanded mutations in their mitochondrial DNA (mtDNA), some of which may drive cancer progression and metastasis. The high prevalence of clonal mutations in tumor mtDNA has commonly led to the assumption that the mitochondrial genome in cancer is genetically unstable, yet this hypothesis has not been experimentally tested. In this study, we directly measured the frequency of non-clonal (random) de novo single base substitutions in the mtDNA of human colorectal cancers. Remarkably, tumor tissue exhibited a decreased prevalence of these mutations relative to adjacent non-tumor tissue. The difference in mutation burden was attributable to a reduction in C∶G to T∶A transitions, which are associated with oxidative damage. We demonstrate that the lower random mutation frequency in tumor tissue was also coupled with a shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, as compared to non-neoplastic colon. Together these findings raise the intriguing possibility that fidelity of mitochondrial genome is, in fact, increased in cancer as a result of a decrease in reactive oxygen species-mediated mtDNA damage. Mitochondria are the intracellular organelles responsible for energy production in eukaryotic cells. They are unique in that they contain their own DNA (mtDNA), which encodes genes important for mitochondrial function and is the cell's only genetic material stored outside the nucleus. Mutations in both nuclear and mtDNA are believed to have a role in tumor growth and metastasis. While it is well established that nuclear DNA has an increased overall burden of mutations in human cancers, this has not been investigated in mtDNA. Here we use a highly sensitive assay to determine mutational load in mtDNA isolated from patient-matched normal and cancerous colonic tissues. Surprisingly, we discovered that the frequency of mutations in mtDNA is actually decreased in tumors relative to healthy tissues, suggesting that, unlike in nuclear DNA, accelerated mutagenesis in mtDNA does not facilitate a cancer's development and may even hinder it. These findings raise the possibility that mitochondrial-targeted cancer therapeutics focused on directly increasing mtDNA damage and mutation might effectively suppress malignant growth.
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影响因子：
2.8
作者：
Arnold, Rebecca S.;Sun, Carrie Q.;Richards, Jendai C.;Grigoriev, Galina;Coleman, Ilsa M.;Nelson, Peter S.;Hsieh, Chia-Ling;Lee, Jae K.;Xu, Zhiheng;Rogatko, Andre;Osunkoya, Adeboye O.;Zayzafoon, Majd;Chung, Leland;Petros, John A.
通讯作者：
Petros, John A.
DOI：
10.1073/pnas.0607057103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Bielas, Jason H.;Loeb, Keith R.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
影响因子：
2.8
作者：
Bielas, JH;Loeb, LA
通讯作者：
Loeb, LA