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Interferon-Gamma-Inducible Protein 16 Inhibits Hepatocellular Carcinoma via Interferon Regulatory Factor 3 on Chemosensitivity

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Abstract

Background and Aim

Previous reports have suggested IFI16 as a tumor suppressor in hepatocellular carcinoma (HC). Nonetheless, the biological significance of IFI16 and its mechanism concerning resistance to cisplatin (DDP) in HC requires further exploration.

Methods

Samples of tumor and corresponding para-carcinoma tissues were acquired from patients with HC. Furthermore, DDP-resistant cell lines of HC, specifically HCC, Huh7 and Hepatoblastoma, HepG3, were generated by gradually increasing the concentration of DDP. Cell apoptosis and DNA damage were evaluated by utilizing flow cytometry assay and TUNEL staining. The interaction between IFI16 and interferon regulatory factor 3 (IRF3) proteins were analyzed using Co-Immunoprecipitation (Co-IP) assay. In vivo assays were conducted by establishing HC subcutaneous xenograft tumor models.

Results

The study found a reduction in IFI16 expression in both HC tissues and DDP-resistant HC cell lines. The binding of IFI16 to IRF3 regulated DNA damage-associated markers in vitro. Overexpression of IFI16 heightened the susceptibility of DDP-induced apoptosis and DNA damage, which was counteracted by IRF3 knockdown, while strengthened by IRF3 overexpression. Moreover, overexpression of IFI16 diminished in vivo DDP-resistant HC tumorigenicity.

Conclusion

In summary, our findings suggest that IFI16 serves as a tumor suppressor in HC by promoting DNA damage via its interaction with IRF3, thereby reversing DDP resistance.

Graphical Abstract

Cisplatin-induced damage in tumor cells, with the involvement of DNA repair, leads to survival of tumor cells, manifesting as drug resistance of the tumor. However, the binding of IRF3 and IFI16 inhibits DNA repair, resulting in the ultimate fate of cell death.

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Funding

This study was supported by Wenzhou Medical University Affiliated Second Hospital, Yuying Children's Hospital Doctoral Research Startup Fund Project.

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Author notes

  1. Wei Lin, Zhiguang Zhao, Wenjun Du, and Zhonglin Ni have contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Diseases, The Second Affiliated Hospital of Wenzhou Medical University, #1111 of Wenzhou Wenzhou Avenue, Longwan District, Wenzhou, Zhejiang, China

    Wei Lin, Chenwei Pan, Peipei Fang, Jie Li, Lu ZhuGe & Shuanghong Jin

  2. Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Zhiguang Zhao

  3. Department of Liver Diseases, Shandong Public Health Clinical Center, Shangdong University, Jinan, Shangdong, China

    Wenjun Du

  4. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Zhonglin Ni

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  1. Wei Lin
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Correspondence to Wei Lin.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University.

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Lin, W., Zhao, Z., Du, W. et al. Interferon-Gamma-Inducible Protein 16 Inhibits Hepatocellular Carcinoma via Interferon Regulatory Factor 3 on Chemosensitivity. Dig Dis Sci 69, 491–501 (2024). https://doi.org/10.1007/s10620-023-08175-x

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  • DOI: https://doi.org/10.1007/s10620-023-08175-x

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