Knock down of APE1 suppressed gastric cancer metastasis via improving immune disorders caused by myeloid-derived suppressor cells

ABSTRACT

Gastric cancer is a highly immunogenic malignancy. Immune tolerance facilitated by myeloid-derived suppressor cells (MDSCs) has been implicated in gastric cancer resistance mechanisms. The potential role of APE1 in regulating gastric cancer metastasis by targeting MDSCs remains uncertain. In this study, the plasmid Plxpsp-mGM-CSF was used to induce high expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in GES-1 cells. For tumor transplantation experiments, AGS, AGS+GM-CSF and AGS+GM-CSF-siAPE1 cell lines were established by transfection, followed by subcutaneous implantation of tumor cells. MDSCs, Treg cells, IgG, CD3 and CD8 levels were assessed. Transfection with siAPE1 significantly inhibited tumor growth compared to the AGS+GM-CSF group. APE1 gene knockdown modulated the immune system in gastric cancer mice, characterized by a decrease in MDSCs and an increase in Treg cells, IgG, CD3 and CD8. In addition, APE1 gene knockdown resulted in decreased levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12). Furthermore, APE1 gene knockdown inhibited proliferation, migration and invasion of AGS and MKN45 cells. AGS-GM-CSF cell transplantation increased MDSC levels and accelerated tumor growth, whereas APE1 knockdown reduced MDSC levels, inhibited tumor growth and attenuated inflammatory infiltration in gastric cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach to the prevention and treatment of gastric cancer, providing new insights into its management.

KEYWORDS:

• Gastric cancer
• MDSCS
• APE1
• AGS
• tumor immune

List of abbreviations

Myeloid-derived suppressor cells (MDSCs), Granulocyte-macrophage colony-stimulating factor (GM-CSF), Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1), Severe combined immunodeficiency (SCID), Immunohistochemical staining (IHC), Enzyme-linked immunosorbent assay (ELISA).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

BZ conceived and designed the experiments; QT, WS, ZB, SG, and CP performed the experiments; BZ wrote the paper. All authors approved for this submission.

Ethical Approval and Consent to participate

Ethical approval was obtained from the institutional ethics committee of The First People’s Hospital of Lianyungang

Availability of data and material

The data and material used to support the findings of this study are included within the manuscript, and the RNA-seq data was uploaded to GEO data base (GSE262050).

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2351629

Additional information

Funding

This work was supported by Doctor Scientific Research Start Fund Project of the First People’s Hospital of Lianyungang [Grant Nos.BS1902] and the Program of Medical Technology of the First People’s Hospital of Lianyungang [Grant Nos.XJ1912].