Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer.
Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer.
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DOI：
10.1158/0008-5472.can-10-3482
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Guo J;Zheng L;Liu W;Wang X;Wang Z;Wang Z;French AJ;Kang D;Chen L;Thibodeau SN;Liu W
线粒体转录因子A（TFAM）是线粒体DNA（mtDNA）复制和转录所必需的。TFAM的破坏导致小鼠心力衰竭和过早衰老。但对TFAM在癌症发展中的作用知之甚少。在这里，我们报告了在散发性结直肠癌（CRC）细胞系和具有微卫星不稳定性（MSI）的原发性肿瘤中TFAM编码单核苷酸重复序列中频繁的移码突变的鉴定，但在微卫星稳定（MSS）CRC细胞系和肿瘤中没有。在具有MSI的CRC细胞中，TFAM截短突变的存在降低了体内和体外的TFAM蛋白水平，并且与mtDNA消耗相关。此外，携带TFAM截短突变的RKO细胞中野生型TFAM的强制过表达抑制细胞增殖并抑制RKO细胞诱导的异种移植肿瘤生长。此外，由于细胞色素B（Cyt B）表达增加及其从线粒体释放，这些细胞对顺铂诱导的凋亡表现出更大的易感性。TFAM与线粒体重链启动子（HSP）之间的相互作用测定显示，突变体TFAM与HSP的结合减少，导致Cyt B转录减少。总的来说，这些数据提供了TFAM截短突变的高发生率导致线粒体拷贝数减少和线粒体不稳定的证据，将大多数具有MSI的CRC与MSS CRC区分开来。这些突变可能在大多数微卫星不稳定CRC的肿瘤发生和顺铂诱导的凋亡抵抗中起重要作用。
The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs.