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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We wish to thank Jia Li, Siyu He and Canping Chen (China Pharmaceutical University) for technical guidance. Also, we wish to thank the help from the following professors of China Pharmaceutical University, Dr. Lei Qiang for gifting plasmids, Dr. Xiaosheng Wang for bioinformation direction and Dr. Zhaoqiu Wu for writing direction. Further, we wish to acknowledge pathologists Hongyan Wu (Nanjing Drum Tower Hospital) and Zhiwen Li (Nanjing Drum Tower Hospital) for the HCC tissue microarray technique and immunoreactive score.
This work was supported by the Key Program of the National Science Foundation of China (81830105); the program of the National Science Foundation of China (81773774).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Pan, D., Yang, W., Zeng, Y. et al. AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma. Oncogene 41, 3846–3858 (2022). https://doi.org/10.1038/s41388-022-02379-7
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