Overexpression of SLAP2 inhibits triple-negative breast cancer progression by promoting macrophage M1-type polarization.
Apoptosis
Macrophage
Proliferation
SLAP2
Triple-negative breast cancer
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 10 2024
29 10 2024
Historique:
received:
27
03
2024
accepted:
09
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Breast cancer is the most common malignant tumor in women, and triple-negative breast cancer (TNBC) is a specific subtype of breast cancer characterized by high invasiveness, high metastatic potential, ease of recurrence, and poor prognosis. Src-like adaptor protein 2 (SLAP2), which can be involved in the regulation of multiple signaling pathways, may be a key target for TNBC. The aim of this study was to investigate the effect of overexpression of SLAP2 on TNBC and to explore the underlying mechanisms. First, we constructed and transfected SLAP2 overexpressing lentivirus based on MDA-MB-231 human TNBC cell line, screened for differential downstream target genes in combination with mRNA high-throughput sequencing (RNA-Seq), and predicted their functions and enriched pathways in conjunction with bioinformatics analysis. The effects of SLAP2 overexpression on macrophage polarization, as well as on tumor proliferation and apoptosis, were assessed by tail vein injection of a stable transfection line of 4T1 cells transfected with SLAP2 overexpressing lentivirus. The effect of SLAP2 on macrophage polarization was assessed by inducing M1/M2 polarization and transfecting SLAP2 overexpressing lentivirus. Meanwhile, a transwell co-culture system was constructed between differently treated macrophages and 4T1 cells to assess the effect of SLAP2 overexpression on the malignant behavior of the cells via macrophage polarization. Overexpression of SLAP2 revealed 179 genes up-regulated and 74 genes down-regulated by mRNA high-throughput sequencing, and the enriched functions and pathways of differential genes were mainly related to immunity response. In vivo experiments revealed that overexpression of SLAP2 inhibited the growth of tumor in nude mice, decreased the expression of ki67 in tumor tissues, and increased the rate of apoptosis in tumor tissues. Meanwhile, we found that overexpression of SLAP2 promoted macrophage polarization toward M1 type and inhibited M2 type polarization in tumors. In vitro experiments further verified its effect on M1/M2 polarization by transfecting SLAP2 overexpressing lentivirus. By transwell co-culture system, we further demonstrated that overexpression of SLAP2 inhibits cell proliferation and invasion, promotes apoptosis, up-regulates the expression of Bax in cells, and down-regulates the expression of Bcl-2 in cells by promoting macrophage M1-type polarization. Overexpression of SLAP2 inhibits TNBC progression by promoting macrophage M1-type polarization.
Identifiants
pubmed: 39472679
doi: 10.1038/s41598-024-75922-z
pii: 10.1038/s41598-024-75922-z
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26035Subventions
Organisme : Hubei Provincial Natural Science Foundation
ID : 2019CFC927
Informations de copyright
© 2024. The Author(s).
Références
Yin, L., Duan, J. J., Bian, X. W. & Yu, S. C. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 22(1), 61. https://doi.org/10.1186/s13058-020-01296-5 (2020).
doi: 10.1186/s13058-020-01296-5
pubmed: 32517735
pmcid: 7285581
Vagia, E., Mahalingam, D. & Cristofanilli, M. The Landscape of targeted therapies in TNBC. Cancers (Basel). 12(4). https://doi.org/10.3390/cancers12040916 (2020).
Li, Y. et al. Recent advances in therapeutic strategies for triple-negative breast cancer. J. Hematol. Oncol. 15(1), 121. https://doi.org/10.1186/s13045-022-01341-0 (2022).
doi: 10.1186/s13045-022-01341-0
pubmed: 36038913
pmcid: 9422136
Wybenga-Groot, L. E. et al. SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function. J. Mol. Biol. 433(8), 166880. https://doi.org/10.1016/j.jmb.2021.166880 (2021).
doi: 10.1016/j.jmb.2021.166880
pubmed: 33617900
Dragone, L. L., Shaw, L. A., Myers, M. D. & Weiss, A. SLAP, a regulator of immunoreceptor ubiquitination, signaling, and trafficking. Immunol. Rev. 232(1), 218–228. https://doi.org/10.1111/j.1600-065X.2009.00827.x (2009).
doi: 10.1111/j.1600-065X.2009.00827.x
pubmed: 19909366
Dragone, L. L. et al. Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner. Proc. Natl. Acad. Sci. U S A. 103(48), 18202–18207. https://doi.org/10.1073/pnas.0608965103 (2006).
doi: 10.1073/pnas.0608965103
pubmed: 17110436
pmcid: 1838730
Kazi, J. U., Agarwal, S., Sun, J., Bracco, E. & Rönnstrand, L. Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling. J. Cell. Sci. 127(Pt 3), 653–662. https://doi.org/10.1242/jcs.140590 (2014).
doi: 10.1242/jcs.140590
pubmed: 24284075
Jin, L. T. The Mechanism of Transcription Factor SLAP2 in Breast cancer [D] (Wuhan University, 2018).
Nalio Ramos, R. et al. Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer. Cell. 185(7), 1189–1207e1125. https://doi.org/10.1016/j.cell.2022.02.021 (2022).
doi: 10.1016/j.cell.2022.02.021
pubmed: 35325594
Pan, Y., Yu, Y., Wang, X. & Zhang, T. Tumor-associated macrophages in tumor immunity. Front. Immunol. 11, 583084. https://doi.org/10.3389/fimmu.2020.583084 (2020).
doi: 10.3389/fimmu.2020.583084
pubmed: 33365025
pmcid: 7751482
Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30. https://doi.org/10.1093/nar/28.1.27 (2000).
doi: 10.1093/nar/28.1.27
pubmed: 10592173
pmcid: 102409
Kanehisa, M., Furumichi, M., Sato, Y., Kawashima, M. & Ishiguro-Watanabe, M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 51, 587–592. https://doi.org/10.1093/nar/gkac963 (2023).
doi: 10.1093/nar/gkac963
Wang, Y. et al. SRC-like adaptor protein negatively regulates wnt signaling in intrahepatic cholangiocarcinoma. Oncol. Lett. 17(3), 2745–2753. https://doi.org/10.3892/ol.2019.9901 (2019).
doi: 10.3892/ol.2019.9901
pubmed: 30854048
pmcid: 6365946
Mansha, M. et al. Functional analyses of src-like adaptor (SLA), a glucocorticoid-regulated gene in acute lymphoblastic leukemia. Leuk. Res. 34(4), 529–534. https://doi.org/10.1016/j.leukres.2009.06.029 (2010).
doi: 10.1016/j.leukres.2009.06.029
pubmed: 19631983
DeNardo, D. G. & Coussens, L. M. Inflammation and breast cancer. Balancing immune response: Crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res. 9(4), 212. https://doi.org/10.1186/bcr1746 (2007).
doi: 10.1186/bcr1746
pubmed: 17705880
pmcid: 2206719
Wei, C. et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol. Cancer. 18(1), 64. https://doi.org/10.1186/s12943-019-0976-4 (2019).
doi: 10.1186/s12943-019-0976-4
pubmed: 30927925
pmcid: 6441214
Genard, G., Lucas, S. & Michiels, C. Reprogramming of tumor-associated macrophages with anticancer therapies: Radiotherapy versus chemo- and immunotherapies. Front. Immunol. 8, 828. https://doi.org/10.3389/fimmu.2017.00828 (2017).
doi: 10.3389/fimmu.2017.00828
pubmed: 28769933
pmcid: 5509958
Mills, C. D. M1 and M2 macrophages: Oracles of health and disease. Crit. Rev. Immunol. 32(6), 463–488. https://doi.org/10.1615/critrevimmunol.v32.i6.10 (2012).
doi: 10.1615/critrevimmunol.v32.i6.10
pubmed: 23428224
Luo, J. et al. Nrf2 deficiency exacerbated CLP-induced pulmonary injury and inflammation through autophagy- and NF-κB/PPARγ-mediated macrophage polarization. Cells 11(23) (2022). https://doi.org/10.3390/cells11233927
Xu, F. et al. Correction: Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling. J. Exp. Clin. Cancer Res. 42(1), 70. https://doi.org/10.1186/s13046-023-02643-y (2023).
doi: 10.1186/s13046-023-02643-y
pubmed: 36959638
pmcid: 10035129
Chen, Y. et al. The mechanism of Alisol B23 acetate inhibiting Lung Cancer: Targeted regulation of CD11b/CD18 to influence macrophage polarization. Drug Des. Devel Ther. 16, 3677–3689. https://doi.org/10.2147/dddt.S375073 (2022).
doi: 10.2147/dddt.S375073
pubmed: 36277599
pmcid: 9583238
Nahar, S. et al. Regression and eradication of Triple-negative breast carcinoma in 4T1 mouse model by combination immunotherapies. Cancers (Basel). 15(8), 2366. https://doi.org/10.3390/cancers15082366 (2023).
doi: 10.3390/cancers15082366
pubmed: 37190294
Koni, M. et al. Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/G-CSF pathway. Pharmacol. Res. 195, 106871. https://doi.org/10.1016/j.phrs.2023.106871 (2023).
doi: 10.1016/j.phrs.2023.106871
pubmed: 37506784