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Carnosic acid nanocluster-based framework combined with PD-1 inhibitors impeded tumorigenesis and enhanced immunotherapy in hepatocellular carcinoma

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Abstract

Clinically, the immune checkpoint inhibitor anti-PD-1 antibody has shown a certain effect in the treatment of hepatocellular carcinoma (HCC), which is limited to a small number of patients with HCC. This study aims to reveal whether carnosic acid nanocluster-based framework (CA-NBF) has a sensitization effect on anti-PD-1 antibody in the treatment of HCC at the cellular and animal levels. MHCC97H cells were treated with CA-NBF, anti-PD-1 and their combination. The effects of CA-NBF and anti-PD-1 on cell proliferation, cell cycle, apoptosis, invasion, and migration were evaluated by MTT assay, flow cytometry, and scratch test. The effects of CA-NBF and anti-PD-1 on Wnt/β-catenin signaling pathway in MHCC97H cells were detected. A BALB/C nude mouse model of hepatocellular carcinoma was established, and the tumor growth was observed at different time points. The expression of cytotoxic T lymphocyte and helper T lymphocyte markers CD8 and CD4 in tumor tissues was detected by immunohistochemistry. Western blotting was used to detect the Wnt/β-catenin signaling pathway proteins (Wnt-3a, β-catenin, and GSK-3β) level in tumor tissues after CA-NBF and anti-PD-1 treatment. CA-NBF activity was significantly higher than CA, which could prominently reduce the proliferation, migration and invasion of MHCC97H cells and enhance apoptosis by inactivating Wnt/β-catenin signaling pathway. CA-NBF combined with anti-PD-1 antibody further enhanced cell proliferation, migration, invasion and pro-apoptosis but had no significant effect on Wnt/β-catenin signaling pathway. CA-NBF in vivo improved the tumor response to PD1 immune checkpoint blockade in HCC, manifested by reducing tumor size and weight, promoting CD4 and CD8 expression. CA-NBF combined with anti-PD-1 have stronger immunomodulatory and anticancer effects without increasing biological toxicity.

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Data availability

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

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Acknowledgements

I would like to express my gratitude to all those who helped me while writing this thesis. I acknowledge the help of my colleagues, Fanpu Ji and Caizhi Fang. They have offered me suggestion in academic studies.

Funding

This study was supported by the Natural Science Foundation of Shaanxi Province (2022SF-451).

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Authors and Affiliations

Authors

Contributions

Xiaoli Jia and Wenhua Wu: project administration and supervision; Junrong Liang, Weiming You, and Wenhua Wu: investigation, conceptualization, and methodology; Xiaokang Wu, Xinyuan He, and Ting Li: investigation, resources, and validation; Yaping Li and Qinhui Feng: formal analysis and data curation; Wenhua Wu: writing—review and editing. All the authors have read and approved the manuscript.

Corresponding authors

Correspondence to Wenhua Wu or Xiaoli Jia.

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Ethics approval

Animal experiments were approved and supervised by the Animal Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University. All methods were carried out in accordance with relevant guidelines and regulations.

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The authors declare there are no competing interests.

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Wu, W., Li, Y., Wu, X. et al. Carnosic acid nanocluster-based framework combined with PD-1 inhibitors impeded tumorigenesis and enhanced immunotherapy in hepatocellular carcinoma. Funct Integr Genomics 24, 5 (2024). https://doi.org/10.1007/s10142-024-01286-2

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  • DOI: https://doi.org/10.1007/s10142-024-01286-2

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