近日,，Molecular Biology and Evolution在線發(fā)表了中國科學(xué)院昆明動物研究所孔慶鵬研究組研究人員的研究成果,。
癌細(xì)胞的快速增殖等特點使得其代謝遠(yuǎn)高于正常細(xì)胞且需要獲取更多的能量，但與正常細(xì)胞不同的是,，癌細(xì)胞即便是在有氧條件下也主要是以產(chǎn)能效率更低地糖酵解方式獲取能量（有氧糖酵解或Warburg效應(yīng)），提示有氧呼吸途徑的作用很可能被嚴(yán)重削弱。而由于線粒體DNA參與編碼有氧呼吸的關(guān)鍵組成部分——呼吸鏈的多個復(fù)合體,，通過對癌組織中線粒體DNA的突變模式及其產(chǎn)生機制的研究，有可能對深入理解伴隨著癌細(xì)胞能量獲取方式的轉(zhuǎn)變所可能帶來的適應(yīng)性變化提供新的證據(jù),。
鑒于此,，博士研究生劉佳等獲取了186例食管癌癌組織及癌旁正常組織的線粒體基因組序列，并將其與已報道的來自各種癌組織樣本的1235條線粒體全基因組序列以及3639條來自一般人群的線粒體基因組序列進(jìn)行了充分的比較研究,。結(jié)果表明,，無論是在食管癌還是其它類型的癌組織中，其線粒體DNA突變模式與一般人群的均明顯不同,。進(jìn)一步分析提示,，癌組織中線粒體DNA其受到的選擇壓力發(fā)生了較為明顯的放松，該結(jié)果與癌細(xì)胞產(chǎn)能方式的轉(zhuǎn)變（有氧呼吸→有氧糖酵解）及其伴隨而來的呼吸鏈功能降低的預(yù)期相吻合,。一系列分析還表明,，前人研究工作中對癌線粒體DNA突變模式存在的相互沖突的觀點,，主要是源自前期報道數(shù)據(jù)中的質(zhì)量問題。
該項工作提示,，大多數(shù)癌線粒體DNA突變很可能僅僅只是選擇壓力放松所產(chǎn)生的結(jié)果,，對于線粒體DNA在癌發(fā)生發(fā)展過程中的真正作用需要有新的認(rèn)識。該項研究獲得了編輯及審稿人的高度評價,，被認(rèn)為“將對本領(lǐng)域產(chǎn)生重要影響”,。（生物谷Bioon.com）
doi:10.1093/molbev/msr290
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Deciphering the signature of selective constraints on cancerous mitochondrial genome
Jia Liu1, Li-Dong Wang, Yan-Bo Sun1, 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.
