Abstract
Loss of expression or protein kinase B (Akt1)-mediated post-translational modification of the RNA binding protein Poly r(C) binding protein 1 (PCBP1) is closely related to metastatic advancement of breast cancer. However, the role of PCBP1 in tumorigenesis is not completely defined. Using a xenograft orthotopic model of breast tumorigenesis (4T1-Pcbp1−/−), we show here that PCBP1 knockdown-induced tumorigenesis is inhibited by activation of the WNT signaling via treating with the glycogen synthase kinase 3 beta inhibitor TWS119, but not the Akt2/Akt3 inhibitor GSK690693. Mass cytometry-based evaluation of the tumor microenvironment (TME) revealed significantly more regulatory T cells (Tregs) and significantly less cytotoxic T cells in 4T1-Pcbp1−/−mice treated with saline control in comparison to mice treated with TWS119. Infiltrating cytotoxic T cells were phenotypically and functionally exhausted. Treatment with TWS119 resulted in rescue of cytotoxic T cell function and inhibition of suppressor activity of Tregs. Using cytotoxic T cells isolated from healthy donors, we show that TWS119-induced WNT signaling-mediated inhibition of cytotoxic T cell expansion is reliant on expression of PCBP1. In conclusion, decreased PCBP1 expression favors breast tumorigenesis by potentiating skewing of tumor infiltrating T cells towards Tregs, thereby effectively suppressing anti-tumor immunity.
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Data related to results presented in this manuscript are either incorporated in the manuscript or will be accessible upon request to the corresponding author.
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This study were supported by the Key R&D Project of Jilin Province Science and Technology Department (20200404144YY) and Jilin Provincial Development and Reform Commission Project (2019C052-5). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Z.Y.Y and G.S. designed this study; W.L.Z and C.W.J carried out experiments and analyzed data; Z.Y.Y and G.S. prepared the manuscript. All authors read and approved the final manuscript.
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Highlights
• PCBP1 functions as the upstream of GSK-3β/WNT signaling during epithelial to mesenchymal transition in breast cancer.
• Activation of WNT signaling by GSK3β inhibitor TWS119 results in functional impairment of Tregs and potentiates effector function of CD8+ T cells
• TWS119-induced WNT signaling-mediated inhibition of cytotoxic T cell expansion is reliant on the expression of PCBP1
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Yang, Zy., Zhang, Wl., Jiang, Cw. et al. PCBP1-mediated regulation of WNT signaling is critical for breast tumorigenesis. Cell Biol Toxicol 39, 2331–2343 (2023). https://doi.org/10.1007/s10565-022-09722-4
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DOI: https://doi.org/10.1007/s10565-022-09722-4