AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer
AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer
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DOI：
10.1172/jci.insight.99976
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发表时间：
2018-06-21
期刊：
影响因子：
8
通讯作者：
Goel, Ajay
中科院分区：
文献类型：
--
作者：
Shigeyasu, Kunitoshi;Okugawa, Yoshinaga;Goel, Ajay
腺苷转肌苷（Adenosine-to-inosine，A-to-I）RNA编辑是一种由腺苷脱氨酶介导的作用于RNA（阿达尔）基因家族的过程，是最近发现的一种在人类癌症中失调的表观遗传修饰。然而，RNA编辑在结直肠癌（CRC）中的临床意义和功能作用仍不清楚。我们系统而全面地研究了来自多个独立CRC患者队列的392例结直肠组织中ADAR 1表达状态和抗酶抑制剂1（AZIN 1）RNA编辑水平的意义，AZIN 1是癌症中最常编辑的基因之一。与相应的正常粘膜相比，结直肠癌组织中ADAR 1表达和AZIN 1 RNA编辑水平均显著升高。高水平的AZIN 1 RNA编辑是总生存期和无病生存期的预后因素，也是淋巴结和远处转移的独立风险因素。此外，升高的AZIN 1编辑确定了高风险的II期CRC患者。从机制上讲，编辑的AZIN 1增强了干性，似乎驱动了转移过程。我们已经证明编辑的AZIN 1作为癌基因和CRC中的潜在治疗靶点发挥作用。此外，AZIN 1 RNA编辑状态可用作CRC患者的临床相关预后指标。
Adenosine-to-inosine (A-to-I) RNA editing, a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family, is a recently discovered epigenetic modification dysregulated in human cancers. However, the clinical significance and the functional role of RNA editing in colorectal cancer (CRC) remain unclear. We have systematically and comprehensively investigated the significance of the expression status of ADAR1 and of the RNA editing levels of antizyme inhibitor 1 (AZIN1), one of the most frequently edited genes in cancers, in 392 colorectal tissues from multiple independent CRC patient cohorts. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues when compared with corresponding normal mucosa. High levels of AZIN1 RNA editing emerged as a prognostic factor for overall survival and disease-free survival and were an independent risk factor for lymph node and distant metastasis. Furthermore, elevated AZIN1 editing identified high-risk stage II CRC patients. Mechanistically, edited AZIN1 enhances stemness and appears to drive the metastatic processes. We have demonstrated that edited AZIN1 functions as an oncogene and a potential therapeutic target in CRC. Moreover, AZIN1 RNA editing status could be used as a clinically relevant prognostic indicator in CRC patients.