Placing mitochondrial DNA mutations within the progression model of type I endometrial carcinoma
Placing mitochondrial DNA mutations within the progression model of type I endometrial carcinoma
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DOI：
10.1093/hmg/ddr146
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发表时间：
2011-06-15
影响因子：
3.5
通讯作者：
Gasparre, Giuseppe
中科院分区：
文献类型：
--
作者：
Guerra, Flora;Kurelac, Ivana;Gasparre, Giuseppe
线粒体DNA（mtDNA）突变已在几乎所有类型的癌症中描述。然而，它们在肿瘤发展和进展中的确切作用和发生时间仍然是一个有争议的问题。一个Vogelstein样模型的进展是建立了子宫内膜癌（EC），然而，线粒体DNA已很少在这些肿瘤的研究，尽管线粒体生物合成增加已被证明是一个标志的I型EC。在这里，我们筛选了一组23 I型EC组织，并匹配典型增生的mtDNA突变和四个抑癌基因/癌基因，即PTEN，KRAS，CTNNB 1和TP 53。总的来说，在69%的病例中发现了mtDNA突变，而在56%的病例中发生了核基因突变事件，表明mtDNA突变可能先于这些基因的遗传不稳定性，这些基因通常参与了从增生到肿瘤的进展。蛋白质表达分析显示，在线粒体生物合成和激活的氧化应激反应机制在肿瘤组织中，但不是在增生，与致病性mtDNA突变的发生相关的增加。我们的研究结果指出，线粒体DNA突变参与EC进展，并解释增加线粒体生物合成的I型EC。最后，由于线粒体DNA突变发生在增生后，它们在遗传不稳定性中的潜在作用是可以预见的。
Mitochondrial DNA (mtDNA) mutations have been described in almost all types of cancer. However, their exact role and timing of occurrence during tumor development and progression are still a matter of debate. A Vogelstein-like model of progression is well established for endometrial carcinoma (EC), however, mtDNA has been scarcely investigated in these tumors despite the fact that mitochondrial biogenesis increase has been shown to be a hallmark of type I EC. Here, we screened a panel of 23 type I EC tissues and matched typical hyperplasia for mutations in mtDNA and in four oncosupressors/oncogenes, namely PTEN, KRAS, CTNNB1 and TP53. Overall, mtDNA mutations were identified in 69% of cases, while mutational events in nuclear genes occurred in 56% of the cases, indicating that mtDNA mutations may precede the genetic instability of these genes canonically involved in progression from hyperplasia to tumor. Protein expression analysis revealed an increase in mitochondrial biogenesis and activation of oxidative stress response mechanisms in tumor tissues, but not in hyperplasia, in correlation with the occurrence of pathogenic mtDNA mutations. Our results point out an involvement of mtDNA mutations in EC progression and explain the increase in mitochondrial biogenesis of type I EC. Last, since mtDNA mutations occur after hyperplasia, their potential role in contributing to genetic instability may be envisioned.