Center for Gastrointestinal Research and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
JCI Insight. 2018 Jun 21;3(12). doi: 10.1172/jci.insight.99976.
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.
腺嘌呤到次黄嘌呤（A-to-I）RNA 编辑是一种由作用于 RNA 的腺苷脱氨酶（ADAR）基因家族介导的表观遗传修饰，在人类癌症中被发现失调。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 ADAR1 的表达状态和最常被编辑的基因之一抗胰酶抑制剂 1（AZIN1）的 RNA 编辑水平在来自多个独立 CRC 患者队列的 392 个结直肠组织中的意义。与相应的正常粘膜相比，CRC 组织中 ADAR1 表达和 AZIN1 RNA 编辑水平均显著升高。高水平的 AZIN1 RNA 编辑成为总生存期和无病生存期的预后因素，并且是淋巴结和远处转移的独立危险因素。此外，升高的 AZIN1 编辑鉴定出高危 II 期 CRC 患者。从机制上讲，编辑后的 AZIN1 增强了干细胞特性，似乎推动了转移过程。我们已经证明，编辑后的 AZIN1 是 CRC 中的癌基因和潜在的治疗靶点。此外，AZIN1 RNA 编辑状态可作为 CRC 患者具有临床相关性的预后指标。
