Department of Biochemistry and Molecular Biology E.Quagliariello, University of Bari, 70126 Bari, Italy.
Hum Mol Genet. 2011 Jun 15;20(12):2394-405. doi: 10.1093/hmg/ddr146. Epub 2011 Apr 5.
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.
线粒体 DNA（mtDNA）突变几乎存在于所有类型的癌症中。然而，它们在肿瘤发生和发展过程中的具体作用和发生时间仍然存在争议。子宫内膜癌（EC）的进展具有 Vogelstein 样模型，然而，尽管已经表明线粒体生物发生的增加是 I 型 EC 的标志，但在这些肿瘤中很少研究 mtDNA。在这里，我们筛选了一组 23 种 I 型 EC 组织和匹配的典型增生，以检测 mtDNA 和四个抑癌基因/原癌基因（即 PTEN、KRAS、CTNNB1 和 TP53）中的突变。总的来说，mtDNA 突变在 69%的病例中被鉴定出来，而核基因中的突变事件在 56%的病例中发生，这表明 mtDNA 突变可能先于这些基因的遗传不稳定性发生，这些基因通常参与从增生到肿瘤的进展。蛋白质表达分析显示，肿瘤组织中线粒体生物发生的增加和氧化应激反应机制的激活，但在增生中没有，这与致病性 mtDNA 突变的发生相关。我们的结果表明 mtDNA 突变参与了 EC 的进展，并解释了 I 型 EC 中线粒体生物发生的增加。最后，由于 mtDNA 突变发生在增生之后，因此可以设想它们在导致遗传不稳定性方面的潜在作用。
