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MBE:癌线粒体DNA突变产生的新机制

2011/12/07 来源:中国科学院
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由于线粒体DNA参与编码有氧呼吸的关键组成部分——呼吸链的多个复合体,通过对癌组织中线粒体DNA的突变模式及其产生机制的研究,有可能对深入理解伴随着癌细胞能量获取方式的转变所可能带来的适应性变化提供新的证据。

癌细胞的快速增殖等特点使得其代谢远高于正常细胞且需要获取更多的能量,但与正常细胞不同的是,癌细胞即便是在有氧条件下也主要是以产能效率更低地糖酵解方式获取能量(有氧糖酵解或Warburg效应),提示有氧呼吸途径的作用很可能被严重削弱。

线粒体

而由于线粒体DNA参与编码有氧呼吸的关键组成部分——呼吸链的多个复合体,通过对癌组织中线粒体DNA的突变模式及其产生机制的研究,有可能对深入理解伴随着癌细胞能量获取方式的转变所可能带来的适应性变化提供新的证据。

鉴于此,中国科学院昆明动物研究所孔庆鹏研究组博士研究生刘佳等获取了186例食管癌癌组织及癌旁正常组织的线粒体基因组序列,并将其与已报道的来自各种癌组织样本的1235条线粒体全基因组序列以及3639条来自一般人群的线粒体基因组序列进行了充分的比较研究。

结果表明,无论是在食管癌还是其它类型的癌组织中,其线粒体DNA突变模式与一般人群的均明显不同。进一步分析提示,癌组织中线粒体DNA其受到的选择压力发生了较为明显的放松,该结果与癌细胞产能方式的转变(有氧呼吸→有氧糖酵解)及其伴随而来的呼吸链功能降低的预期相吻合。一系列分析还表明,前人研究工作中对癌线粒体DNA突变模式存在的相互冲突的观点,主要是源自前期报道数据中的质量问题。

该项工作提示,大多数癌线粒体DNA突变很可能仅仅只是选择压力放松所产生的结果,对于线粒体DNA在癌发生发展过程中的真正作用需要有新的认识。该项研究获得了编辑及审稿人的高度评价,被认为“将对本领域产生重要影响”。

该研究成果已在线发表于分子进化领域期刊Molecular Biology and Evolution上。


Deciphering the signature of selective constraints on cancerous mitochondrial genome

Jia Liu, Li-Dong Wang, Yan-Bo Sun, En-Min Li, Li-Yan Xu, Ya-Ping Zhang, Yong-Gang Yao and Qing-Peng Kong

In accordance with the hypothesis that cancer formation is a process of somatic evolution driven by natural selection, signature of positive selection has been detected on a number of cancer-related nuclear genes. It remains however controversial whether a similar selective pressure has also acted on mitochondrial DNA (mtDNA), a small molecule in mitochondrion but being suggested to play an important role in tumorigenesis by altering oxidative phosphorylation. To better understand the mutational pattern on cancerous mtDNA and decipher the genetic signature left by natural selection, a total of 186 entire mitochondrial genomes of cancerous and adjacent normal tissues from 93 esophageal cancer patients were obtained and extensively studied. Our results revealed that the observed mutational pattern on the cancerous mtDNAs might be best explained as relaxation of negative selection. Taken into account additional 1,235 cancerous (nearly) complete mtDNA sequences retrieved from the literature, our results suggested that the relaxed selective pressure was most likely explanation for the accumulation of mtDNA variation in different types of cancer. This notion is in good agreement with the observation that aerobic glycolysis, instead of mitochondrial respiration, plays the key role in generating energy in cancer cells. Furthermore, our study provided solid evidence demonstrating that problems in some of the published cancerous mtDNA data well explained the previously contradictory conclusions about the selective pressure on cancer mtDNA, thus serving as a paradigm emphasizing the importance of data quality in affecting our understanding on the role of mtDNA in tumorigenesis.

文献链接http://mbe.oxfordjournals.org/content/early/2011/11/29/molbev.msr290.abstract?etoc

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