A-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms. ADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented. ADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43–9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1. The current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway.

中文翻译：

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A-to-I RNA 编辑酶 ADAR1 的抑制通过调节 Keap1/Nrf2 通路使肝细胞癌细胞对氧化应激敏感

A-to-I RNA 编辑是肝细胞癌 (HCC) 中丰富的转录后修饰事件。有证据表明，作用于 RNA 1 (ADAR1) 的腺苷脱氨酶与氧化应激相关，氧化应激是 HCC 发病机制的关键因素。本研究调查了 ADAR1 对 HCC 生存和氧化应激的影响及其潜在机制。通过实时定量 PCR 和免疫组织化学检测了 50 个 HCC 和正常组织中的 ADAR1 表达。为了稳定敲低或过表达 ADAR1，将携带 sh-ADAR1 或 ADAR1 过表达的腺相关病毒载体转染到 HepG2 和 SMMC-7721 细胞中。将转染的细胞暴露于氧化应激激动剂 tBHP 或索拉非尼 Bay 43-9006。测量细胞增殖、凋亡和氧化应激，并进行肿瘤异种移植实验。ADAR1 在 HCC 中表达上调，并与不良的临床结果相关。ADAR1 缺陷会减弱 HCC 细胞的增殖和肿瘤生长并增强细胞凋亡。此外，它的缺失促进了细胞内ROS的积累，并提高了Keap1的表达并降低了Nrf2的表达。在 ADAR1 缺失的情况下，细胞内 GSH 含量和 SOD 活性降低，MDA 含量增加。当 ADAR1 过表达时观察到相反的结果。同时抑制 ADAR1 进一步加剧了 tBHP 和 Bay 43-9006 对存活、凋亡、细胞内 ROS 积累和 Keap1/Nrf2 通路的影响。目前的研究表明，ADAR1是HCC细胞生存和氧化应激所必需的，靶向ADAR1可能通过调节Keap1/Nrf2通路使HCC细胞对氧化应激敏感。