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Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21

Gene Therapy volume 30, pages 88–100 (2023)Cite this article

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Abstract

Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.

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Fig. 1: The expression levels of PD-L1 or exosomal PD-L1 were upregulated in esophageal cancer.
Fig. 2: Isolation and characterization of exosomes.
Fig. 3: Uptake of EC-9706R-exo by 9706 cells.
Fig. 4: Exosomes from EC-9706R contribute to drug resistance in ESCC.
Fig. 5: Exosomal PD-L1 enhanced paclitaxel resistance in ESCC through STAT3/miR-21.
Fig. 6: Exosomal PD-L1 mediated paclitaxel resistance in ESCC through modulation PTEN/Akt pathway.
Fig. 7: Exosomal PD-L1 promotes drug resistance of esophageal cancer cells in vivo.
Fig. 8: Exosomal PD-L1 induces apoptosis and enhances paclitaxel sensitivity.
Fig. 9: Schematic of the potential role of exosomal PD-L1 in paclitaxel resistance in esophageal squamous cell carcinoma.

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Data availability

The data supporting the findings of this study are available within the article. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81972571), Key Science and Technology Program of Henan Province (212102310168) and Innovation Scientists and Technicians Troop Construction Projects of Henan Province (CXTD2017071).

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Authors and Affiliations

  1. School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang, China

    Haojie Wang, Juanjuan Xu, Mengxi Zhu, Tingting Yang, Ruolin Shi & Gaofeng Liang

  2. Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, The First Affiliated Hospital School of Clinical Medicine of Henan University of Science and Technology, Luoyang, China

    Yijun Qi, Zijun Lan & Shegan Gao

  3. Key Laboratory of Cell Behavior, Medical College of Xuchang University, Xuchang, China

    Qiwei Liu

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Contributions

HJW: Conceptualization, investigation, validation, formal analysis, writing—original draft, writing-review and editing. YJQ: Conceptualization, writing—original draft, formal analysis, supervision. ZJL and JJX: Investigation, validation, and data curation. QWL: Investigation, validation, and funding acquisition. MXZ, TTY, and RLS: Validation, formal analysis. SGG: Conceptualization, investigation supervision. GFL: Conceptualization, writing-review and editing, supervision, project administration, and funding acquisition.

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Correspondence to Shegan Gao or Gaofeng Liang.

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All patients signed informed consents for the use and analysis of clinical data before surgery. The collection of blood samples and the acquisition of clinical data were approved by the Institutional Review Board of Henan University of Science and Technology.

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Wang, H., Qi, Y., Lan, Z. et al. Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21. Gene Ther 30, 88–100 (2023). https://doi.org/10.1038/s41434-022-00331-8

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