2. Academic Validation
  3. 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

  • Oncogene. 2022 Jul;41(31):3846-3858. doi: 10.1038/s41388-022-02379-7.
Di Pan  # 1 2,  Wanwan Yang  # 1,  Yao Zeng  # 1,  Hongkun Qin 1,  Yuting Xu 1,  Yanping Gui 1,  Xiangshan Fan 3,  Geng Tian 1,  Yujia Wu 1,  Haopeng Sun 4,  Yuting Ye 1,  Shihe Yang 1,  Jieying Zhou 5,  Qinglong Guo 6 7,  Li Zhao 8
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
  • 2 The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
  • 3 Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University School of Medicine, Nanjing, 210000, Jiangsu, China.
  • 4 Department of Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
  • 5 Department of chemistry and biochemistry, Florida International University, Miami, FL, USA.
  • 6 Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China. anticancer_drug@163.com.
  • 7 Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. anticancer_drug@163.com.
  • 8 Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China. zhaoli@cpu.edu.cn.
  • # Contributed equally.
PMID: 35773412 DOI: 10.1038/s41388-022-02379-7
Abstract

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.

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