AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma
AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma
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DOI：
10.1038/s41388-022-02379-7
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发表时间：
2022-06-30
期刊：
影响因子：
8
通讯作者：
Zhao, Li
中科院分区：
文献类型：
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作者：
Pan, Di;Yang, Wanwan;Zhao, Li
醛酮还原酶家族1成员C3 （AKR1C3）在多种肿瘤中起着重要作用，其在肝细胞癌（HCC）患者中的表达升高。然而，AKR1C3在HCC中的生物学功能尚不清楚。在这里，我们通过体外和体内模型研究了AKR1C3在肝癌发生中的作用。我们确定AKR1C3在预后不良的HCC组织中经常升高。在体外和体内研究了AKR1C3构建的基因操作细胞，以突出野生型AKR1C3和突变型AKR1C3的促肿瘤生长。我们观察到在小鼠瘤内注射AKR1C3 shRNA有很好的治疗效果。机械地，我们证明了转录因子异二聚体NRF2/MAFG能够直接结合到AKR1C3启动子上以激活其转录。此外，AKR1C3通过降低PARP1的泛素化来稳定PARP1，从而导致HCC细胞增殖和顺铂的低敏感性。此外，我们发现AKR1C3的致瘤作用是非催化依赖性的，NRF2/MAFG-AKR1C3-PARP1轴可能是HCC中重要的增殖途径之一。总之，阻断AKR1C3表达对HCC具有潜在的治疗益处。
Aldo-keto reductase family 1 member C3 (AKR1C3) serves as a contributor to numerous kinds of tumors, and its expression is elevated in patients with hepatocellular carcinoma (HCC). However, the biological function of AKR1C3 in HCC remains unclear. Here we investigated the role of AKR1C3 in liver carcinogenesis using in vitro and in vivo models. We determined that AKR1C3 is frequently increased in HCC tissues with poor prognosis. Genetically manipulated cells with AKR1C3 construction were examined to highlight the pro-tumoral growth of both wild-type AKR1C3 and mutant in vitro and in vivo. We observed promising treatment effects of AKR1C3 shRNA by intratumoral injection in mice. Mechanically, we demonstrated that the transcription factor heterodimer NRF2/MAFG was able to bind directly to AKR1C3 promoter to activate its transcription. Further, AKR1C3 stabilized PARP1 by decreasing its ubiquitination, which resulted in HCC cell proliferation and low sensitivity of Cisplatin. Moreover, we discovered that the tumorigenic role of AKR1C3 was non-catalytic dependent and the NRF2/MAFG-AKR1C3-PARP1 axis might be one of the important proliferation pathways in HCC. In conclusion, blockage of AKR1C3 expression provides potential therapeutic benefits against HCC.