ADAR1和AZIN1的RNA编辑发挥癌基因功能，并促成子宫内膜癌的永生化。

ADAR1 and AZIN1 RNA editing function as an oncogene and contributes to immortalization in endometrial cancer.

作者信息

Nakamura Keiichiro, Shigeyasu Kunitoshi, Okamoto Kazuhiro, Matsuoka Hirofumi, Masuyama Hisashi

机构信息

Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

出版信息

Gynecol Oncol. 2022 Aug;166(2):326-333. doi: 10.1016/j.ygyno.2022.05.026. Epub 2022 Jun 11.

DOI:10.1016/j.ygyno.2022.05.026

PMID:35697535

Abstract

OBJECTIVE

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role and clinical significance in endometrial cancer (EC) remain unclear.

METHODS

Adenosine Deaminase family Acting on RNA1 (ADAR1) expression and Antizyme inhibitor 1 (AZIN1) RNA editing were examined to clarify the correlation with clinicopathological parameters and prognosis in EC patients. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in JHUCS-1 and TU-ECS-1 EC cell lines.

RESULTS

ADAR1 showed significant association with worse histology (P = 0.006), and lymph vascular space involvement (P = 0.049) in EC. The level of AZIN1 RNA editing was also significantly associated with worse histology (P = 0.012). ADAR1 expression was significantly correlated with AZIN1 RNA editing level (R = 0.729, R = 0.547, P < 0.001). Multivariate analysis indicated that higher ADAR1 expression along with AZIN1 RNA editing is an independent predictor of prognosis in EC patients (P = 0.015). Knockdown of ADAR1 led to increased MDA-5, RIG-I, PKR, and IRF-7 expression, which in turn resulted in increased levels of Bak and apoptosis in EC cells.

CONCLUSIONS

High ADAR1 expression along with AZIN1 RNA editing could be a predictor of worse prognosis in EC. ADAR1 could be a potential therapeutic target in EC patients.

摘要

目的

腺苷到肌苷（A到I）的RNA编辑是一种最近被描述的表观遗传修饰，被认为是人类癌症中的关键致癌机制。然而，其在子宫内膜癌（EC）中的功能作用和临床意义仍不清楚。

方法

检测RNA特异性腺苷脱氨酶1（ADAR1）的表达以及抗酶抑制剂1（AZIN1）的RNA编辑情况，以阐明其与EC患者临床病理参数及预后的相关性。在JHUCS-1和TU-ECS-1 EC细胞系中研究ADAR1基因敲低后的生物学功能和抑制作用。

结果

ADAR1与EC中较差的组织学（P = 0.006）和淋巴管间隙浸润（P = 0.049）显著相关。AZIN1的RNA编辑水平也与较差的组织学显著相关（P = 0.012）。ADAR1表达与AZIN1的RNA编辑水平显著相关（R = 0.729，R = 0.547，P < 0.001）。多变量分析表明，较高的ADAR1表达以及AZIN1的RNA编辑是EC患者预后的独立预测指标（P = 0.015）。敲低ADAR1会导致MDA-5、RIG-I、PKR和IRF-7表达增加，进而导致EC细胞中Bak水平升高和细胞凋亡增加。