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Potential therapeutic target of EGF on bile duct ligation model and biliary atresia children

Pediatric Research volume 94, pages 1297–1307 (2023)Cite this article

Abstract

Background

The pathogenesis of liver fibrosis in biliary atresia (BA) is unclear. Epidermal growth factor (EGF) plays a vital role in liver fibrosis. This study aims to investigate the expression of EGF and the mechanisms of its pro-fibrotic effects in BA.

Methods

EGF levels in serum and liver samples of BA and non-BA children were detected. Marker proteins of EGF signaling and epithelial-mesenchymal transition (EMT) in liver sections were evaluated. Effects of EGF on intrahepatic cells and the underlying mechanisms were explored in vitro. Bile duct ligation (BDL) mice with/without EGF antibody injection were used to verify the effects of EGF on liver fibrosis.

Results

Serum levels and liver expression of EGF elevated in BA. Phosphorylated EGF receptor (p-EGFR) and extracellular regulated kinase 1/2 (p-ERK1/2) increased. In addition, EMT and proliferation of biliary epithelial cells were present in BA liver. In vitro, EGF induced EMT and proliferation of HIBEpic cells and promoted IL-8 expression in L-02 cells by phosphorylating ERK1/2. And EGF activated LX-2 cells. Furthermore, EGF antibody injection reduced p-ERK1/2 levels and alleviated liver fibrosis in BDL mice.

Conclusion

EGF is overexpressed in BA. It aggravates liver fibrosis through EGF/EGFR-ERK1/2 pathway, which may be a therapeutic target for BA.

Impact

  • The exact pathogenesis of liver fibrosis in BA is unknown, severely limiting the advancement of BA treatment strategies.

  • This study revealed that serum and liver tissue levels of EGF were increased in BA, and its expression in liver tissues was correlated with the degree of liver fibrosis. EGF may promote EMT and proliferation of biliary epithelial cells and induce IL-8 overexpression in hepatocytes through EGF/EGFR-ERK1/2 signaling pathway. EGF can also activate HSCs in vitro.

  • The EGF/EGFR-ERK1/2 pathway may be a potential therapeutic target for BA.

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Fig. 1: Serum levels and liver mRNA expression of EGF were higher in BA children, and the latter was related to liver fibrosis, and p-EGFR levels were elevated in the BA liver.
Fig. 2: EMT and proliferation of biliary epithelial cells present in BA.
Fig. 3: EGF induced EMT and proliferation of HIBEpic cells.
Fig. 4: EGF promoted the EMT process by activating the ERK1/2 pathway in HIBEpic cells.
Fig. 5: EGF promoted IL-8 expression in L-02 cells by activating the ERK1/2 pathway, and EGF activated LX-2 cells.
Fig. 6: Liver fibrosis alleviated, and the levels of EGF and p-ERK1/2 and the EMT process were decreased after EGF antibody injection in BDL mice.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This study was funded by Major Special Projects of Public Health Science and Technology in Tianjin (21ZXGWSY00070) and Xinjiang Uygur Autonomous Region Science Foundation Projects (2021D01A38).

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Author notes

  1. These authors contributed equally: Qipeng Zheng, Mengdi Li.

Authors and Affiliations

  1. Graduate College, Tianjin Medical University, Tianjin, 300070, China

    Qipeng Zheng, Mengdi Li, Lingzhi Chen, Cong Zhang, Yilin Zhao, Gengxin Liu & Fang Yang

  2. Department of General Surgery, Tianjin Children’s Hospital, Tianjin, 300134, China

    Qipeng Zheng, Mengdi Li, Lingzhi Chen, Cong Zhang, Yilin Zhao, Gengxin Liu, Fang Yang & Jianghua Zhan

Authors
  1. Qipeng Zheng
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  4. Cong Zhang
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Contributions

Q.Z. and M.L. contributed to design, data acquisition and analysis, drafted the manuscript, and critically revised the manuscript; L.C. contributed to data acquisition, analysis, and interpretation; C.Z. contributed to data acquisition and analysis; Y.Z. contributed to data acquisition and analysis; G.L. contributed to data acquisition; F.Y. contributed to data acquisition; J.Z. contributed to the conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript.

Corresponding author

Correspondence to Jianghua Zhan.

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The authors declare no competing interests.

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Consent to participate was obtained from guardians of all enrolled children.

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Zheng, Q., Li, M., Chen, L. et al. Potential therapeutic target of EGF on bile duct ligation model and biliary atresia children. Pediatr Res 94, 1297–1307 (2023). https://doi.org/10.1038/s41390-023-02592-4

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