Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers.
Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers.
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DOI：
10.1038/onc.2015.473
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发表时间：
2016-08-04
期刊：
影响因子：
8
通讯作者：
Kashina A
中科院分区：
文献类型：
--
作者：
Rai R;Zhang F;Colavita K;Leu NA;Kurosaka S;Kumar A;Birnbaum MD;Győrffy B;Dong DW;Shtutman M;Kashina A
精氨酸化是由精氨酸基转移酶(ATE1)介导的一种新的翻译后修饰，对哺乳动物胚胎发育和细胞骨架的调节是必不可少的。在这里，我们发现ATE1基因敲除的胚胎成纤维细胞表现出致瘤特性，包括异常快速的非接触生长，形成细胞-细胞接触的能力降低，以及染色体异常。与野生型成纤维细胞不同，ATE1基因敲除的成纤维细胞可以在Matrigel中形成大的集落并表现出侵袭行为。此外，在免疫受损小鼠的皮下异种移植试验中，Ate1基因敲除细胞形成肿瘤。这些细胞的异常生长可以通过重新引入稳定表达的特定ATE1亚型来部分挽救，这也降低了这些细胞形成肿瘤的能力。肿瘤阵列研究和生物信息学分析表明，ATE1在几种类型的人类癌症样本中在蛋白质水平上下调，其转录水平与转移进展和患者生存呈负相关。我们的结论是，Ate1基因敲除导致了培养的成纤维细胞的致癌转化，这表明除了已知的活性外，Ate1基因对肿瘤的抑制也是必不可少的，也可能参与了抑制转移生长的过程。
Arginylation is an emerging posttranslational modification mediated by arginyltransferase (ATE1) that is essential for mammalian embryogenesis and regulation of the cytoskeleton. Here, we discovered that Ate1 knockout embryonic fibroblasts exhibit tumorigenic properties, including abnormally rapid contact-independent growth, reduced ability to form cell-cell contacts, and chromosomal aberrations. Ate1 knockout fibroblasts can form large colonies in Matrigel and exhibit invasive behavior, unlike wild type fibroblasts. Furthermore, Ate1 knockout cells form tumors in subcutaneous xenograft assays in immunocompromised mice. Abnormal growth in these cells can be partially rescued by reintroduction of stably expressed specific Ate1 isoforms, which also reduce the ability of these cells to form tumors. Tumor array studies and bioinformatics analysis show that Ate1 is down-regulated in several types of human cancer samples at the protein level, and that its transcription level inversely correlates with metastatic progression and patient survival. We conclude that Ate1 knockout results in carcinogenic transformation of cultured fibroblasts, suggesting that in addition to its previously known activities Ate1 gene is essential for tumor suppression and also likely participates in suppression of metastatic growth.