AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma.
AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma.
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AHR 介导与肝细胞癌相关的黄曲霉毒素 B1 毒性
DOI：
10.1038/s41392-021-00713-1
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发表时间：
2021-08-09
影响因子：
39.3
通讯作者：
Jiao Y
中科院分区：
文献类型：
--
作者：
Zhu Q;Ma Y;Liang J;Wei Z;Li M;Zhang Y;Liu M;He H;Qu C;Cai J;Wang X;Zeng Y;Jiao Y
黄曲霉毒素暴露是促进肝炎病毒感染个体发生原发性肝细胞癌（HCC）的关键因素。然而，导致其在肝细胞中生物活化和随后毒性的分子途径尚未明确。在这里，我们进行了全基因组CRISPR-Cas9遗传筛选，以识别黄曲霉毒素B1（AFB 1）靶标。其中最重要的命中是芳烃受体（AHR），一个配体结合转录因子调节细胞代谢，分化和immunity. AHR缺陷细胞耐受高浓度的AFB 1，其中AFB 1加合物的形成显着减少。AFB_1通过直接结合AHR的N端而引发AHR的核转位。AHR还可介导AFB 1诱导的P450蛋白表达。从AFB 1-HCC患者获得的原发性肿瘤切片中AHR表达也升高，这与临床相关免疫调节因子PD-L1的上调平行。最后，抗PD-L1治疗在源自异位表达AHR的细胞的HCC异种移植物中表现出更大的功效。这些结果表明，AHR是与HCC相关的AFB 1毒性所必需的，并暗示抗PD-L1免疫抑制方案是治疗AFB 1相关HCC的治疗选择。
Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity.AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.
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