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ZEB1 serves an oncogenic role in the tumourigenesis of HCC by promoting cell proliferation, migration, and inhibiting apoptosis via Wnt/β-catenin signaling pathway

Acta Pharmacologica Sinica volume 42, pages 1676–1689 (2021)Cite this article

Abstract

Zinc finger E-box-binding homeobox 1 (ZEB1), a functional protein of zinc finger family, was aberrant expressed in many kinds of liver disease including hepatic fibrosis and Hepatitis C virus. Bioinformatics results showed that ZEB1 was abnormally expressed in HCC tissues. However, to date, the potential regulatory role and molecular mechanisms of ZEB1 are still unclear in the occurrence and development of HCC. This study demonstrated that the expression level of ZEB1 was significantly elevated both in liver tissues of HCC patients and cell lines (HepG2 and SMMC-7721 cells). Moreover, ZEB1 could promote the proliferation, migration, and invasion of HCC cells. On the downstream regulation mechanism, ZEB1 could activate the Wnt/β-catenin signaling pathway by upregulating the protein expression levels of β-catenin, c-Myc, and cyclin D1. Novel studies showed that miR-708 particularly targeted ZEB1 3′-UTR regions and inhibited the HCC cell proliferation, migration, and invasion. Furthermore, results of nude mice experiments of HCC model indicated that miR-708 could inhibit tumor growth and xenograft metastasis model was established to validate that miR-708 could inhibit HCC cell metastasis through tail-vein injection in vivo. Together, the study suggested that ZEB1 modulated by miR-708 might be a potential therapeutic target for HCC therapy.

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Fig. 1: ZEB1 was aberrantly expressed in human HCC tissues.
Fig. 2: ZEB1 promoted the proliferation of HCC cells.
Fig. 3: ZEB1 promoted the process of EMT in HCC.
Fig. 4: MiR-708 promoted the apoptosis of HCC cells.
Fig. 5: MiR-708 inhibited the migration and invasion of HCC cells.
Fig. 6: ZEB1 activated Wnt/β-catenin signaling pathway in HCC cells.
Fig. 7: MiR-708 inhibited tumor growth in nude mice of HCC model.
Fig. 8: MiR-708 inhibited the process of EMT in HCC.

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (Nos. 81700522, 81602344), the fund of Anhui Medical University doctoral start research (No. 0601067101), Anhui Provincial Natural Science Foundation (1704a0802161, 1808085MH235). The fund of Anhui Science and Technology Department Soft Science Project (1607a0202062). We would like to thank Dr Su-wen Li, Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University for providing us with patient medical records and liver samples.

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  1. These authors contributed equally: Liang-yun Li, Jun-fa Yang, Fan Rong

Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Liang-yun Li, Fan Rong, Zhi-pan Luo, Shuang Hu, Rui Yao, Xiao-wen Feng, Jun Li & Tao Xu

  2. Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China

    Liang-yun Li, Fan Rong, Zhi-pan Luo, Shuang Hu, Rui Yao, Xiao-wen Feng, Jun Li & Tao Xu

  3. Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China

    Jun-fa Yang & Rui Yao

  4. Lujiang County People’s Hospital of Anhui Province, Hefei, 231500, China

    Fan Rong

  5. The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China

    Zhi-pan Luo, Ying Wu & Wei-hao Kong

  6. Department of Pharmocology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China

    Hui Fang

  7. First Clinical Medical College of Anhui Medical University, Hefei, 230032, China

    Bang-jie Chen

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Contributions

LYL and JFY performed the cell experiment and analyzed the data. FR and ZPL performed the animal experiments. TX and JL designed, supervised and wrote the manuscript. SH, YW and HF provided a series of experimental instructions and help. WHK and RY do TCGA data analysis. XWF and BJC contributed new reagents or analytic tools. All authors approved the final version of the manuscript.

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Correspondence to Tao Xu.

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Li, Ly., Yang, Jf., Rong, F. et al. ZEB1 serves an oncogenic role in the tumourigenesis of HCC by promoting cell proliferation, migration, and inhibiting apoptosis via Wnt/β-catenin signaling pathway. Acta Pharmacol Sin 42, 1676–1689 (2021). https://doi.org/10.1038/s41401-020-00575-3

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  • DOI: https://doi.org/10.1038/s41401-020-00575-3

Keywords

  • ZEB1
  • HCC
  • miR-708
  • Wnt/β-catenin
  • xenograft metastasis

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