2. Academic Validation
  3. AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma

AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma

  • Signal Transduct Target Ther. 2021 Aug 9;6(1):299. doi: 10.1038/s41392-021-00713-1.
Qing Zhu  # 1,  Yarui Ma  # 1,  Junbo Liang  # 2,  Zhewen Wei  # 3,  Mo Li 1,  Ying Zhang 1,  Mei Liu 1,  Huan He 1,  Chunfeng Qu 1,  Jianqiang Cai 3,  Xiaobing Wang 4 5,  Yixin Zeng 6 7,  Yuchen Jiao 8 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
  • 3 Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 5 Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. [email protected].
  • 6 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 8 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 9 Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. [email protected].
  • 10 Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 34373448 DOI: 10.1038/s41392-021-00713-1
Abstract

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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