Wang Houhong, Wei Xiaoyu, Liu Lu, Zhang Junfeng, Li Heng
Department of General Surgery, The First Hospital Affiliated to Fuyang Normal University, Fuyang, 236006, Anhui, China.
Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, 236800, Anhui, China.
Exp Hematol Oncol. 2024 Mar 11;13(1):30. doi: 10.1186/s40164-024-00494-7.
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.
A到I RNA编辑是肝细胞癌（HCC）中一种丰富的转录后修饰事件。有证据表明，作用于RNA 1的腺苷脱氨酶（ADAR1）与氧化应激相关，而氧化应激是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50例HCC组织和正常组织中ADAR1的表达。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。将转染后的细胞暴露于氧化应激激动剂叔丁基过氧化氢（tBHP）或索拉非尼（Bay 43-9006）。检测细胞增殖、凋亡和氧化应激，并进行肿瘤异种移植实验。
ADAR1在HCC中上调，且与不良临床结局相关。ADAR1缺乏减弱了HCC细胞的增殖和肿瘤生长，并增强了细胞凋亡。此外，其缺失促进了细胞内活性氧（ROS）积累，提高了Keap1表达并降低了Nrf2表达。在没有ADAR1的情况下，细胞内谷胱甘肽（GSH）含量和超氧化物歧化酶（SOD）活性降低，丙二醛（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对细胞生存、凋亡、细胞内ROS积累和Keap1/Nrf2途径的影响。
当前研究揭示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途径使HCC细胞对氧化应激敏感。
