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The NQO1/p53/SREBP1 axis promotes hepatocellular carcinoma progression and metastasis by regulating Snail stability

Oncogene volume 41, pages 5107–5120 (2022)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, and its abnormal metabolism affects the survival and prognosis of patients. Recent studies have found that NAD(P)H quinone oxidoreductase-1 (NQO1) played an important role in tumor metabolism and malignant progression. However, the molecular mechanisms by which NQO1 regulates lipid metabolism during HCC progression remain unclear. In this study, bioinformatics analysis and immunohistochemical results showed that NQO1 was highly expressed in HCC tissues and its high expression was closely related to the poor prognosis of HCC patients. Overexpression of NQO1 promoted the cell proliferation, epithelial-to-mesenchymal transition (EMT) process, and angiogenesis of HCC cells. Luciferase reporter assay further revealed that NQO1/p53 could induce the transcriptional activity of SREBP1, consequently regulating HCC progression through lipid anabolism. In addition, Snail protein was stabilized by NQO1/p53/SREBP1 axis and triggered the EMT process, and participated in the regulatory role of NQO1/p53/SREBP1 axis in HCC. Together, these data indicated that NQO1/SREBP1 axis promoted the progression and metastasis of HCC, and might be a potential therapeutic target for HCC.

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Fig. 1: NQO1 expression was upregulated in HCC tissues and associated with poor outcomes.
Fig. 2: NQO1 accelerated HCC cell proliferation and inhibited autophagy in vitro, and promoted tumorigenesis in vivo.
Fig. 3: NQO1 accelerated the metastasis of HCC cells via EMT process in vitro and in vivo.
Fig. 4: NQO1 promoted angiogenesis in HCC cells, and accelerated the growth and migration of HUVECs.
Fig. 5: NQO1 regulated lipid anabolism in HCC cells.
Fig. 6: NQO1/p53 regulated HCC progression and metastasis through SREBP1.
Fig. 7: NQO1/p53/SREBP1 posttranslationally regulated Snail protein stability in HCC.
Fig. 8: NQO1/SREBP1 axis might be a reliable prognostic biomarker for patients with HCC.

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Funding

This research was supported by the Projects of Science and Technology Department of Jilin Province (No.210101207, No.202002021JC), the National Natural Science Foundation of China (No.31760313), the Fund of Tumen River Scholar Project.

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  1. Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, China

    Xinyue Wang, Ying Liu, Anna Han, Chunxiao Tang, Ran Xu, Linyuan Feng, Yang Yang, Liyan Chen & Zhenhua Lin

  2. Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, China

    Xinyue Wang, Linyuan Feng, Yang Yang & Zhenhua Lin

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Z-HL and YY were involved in conception and design of the study, X-YW and YL performed in vitro experiments and drafting of the manuscript; Y.L., C-XT, and RX performed in vivo experiments and data analysis; X-YW, L-YF, and A-NH were involved in performing experiments and statistical analysis; Z-HL, L-YC, and YY were manuscript revisions. All authors listed approved the final version of the manuscript.

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Correspondence to Zhenhua Lin.

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Wang, X., Liu, Y., Han, A. et al. The NQO1/p53/SREBP1 axis promotes hepatocellular carcinoma progression and metastasis by regulating Snail stability. Oncogene 41, 5107–5120 (2022). https://doi.org/10.1038/s41388-022-02477-6

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