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http://purl.uniprot.org/citations/35974411http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35974411http://www.w3.org/2000/01/rdf-schema#comment"

Background

B-cell acute lymphoblastic leukemia (B-ALL) comprises over 85% of all acute lymphoblastic leukemia (ALL) cases and is the most common childhood malignancy. Although the 5 year overall survival of patients with B-ALL exceeds 90%, patients with relapsed or refractory B-ALL may suffer from poor prognosis and adverse events. The axon guidance factor netrin-1 has been reported to be involved in the tumorigenesis of many types of cancers. However, the impact of netrin-1 on B-ALL remains unknown.

Methods

The expression level of netrin-1 in peripheral blood samples of children with B-ALL and children without neoplasia was measured by enzyme-linked immunosorbent assay (ELISA) kits. Then, CCK-8 cell proliferation assays and flow cytometric analysis were performed to detect the viability and apoptosis of B-ALL cells (Reh and Sup B15) treated with exogenous recombinant netrin-1 at concentrations of 0, 25, 50, and 100 ng/ml. Furthermore, co-immunoprecipitation(co-IP) was performed to detect the receptor of netrin-1. UNC5B expression interference was induced in B-ALL cells with recombinant lentivirus, and then CCK-8 assays, flow cytometry assays and western blotting assays were performed to verify that netrin-1 might act on B-ALL cells via the receptor Unc5b. Finally, western blotting and kinase inhibitor treatment were applied to detect the downstream signaling pathway.

Results

Netrin-1 expression was increased in B-ALL, and netrin-1 expression was upregulated in patients with high- and intermediate-risk stratification group of patients. Then, we found that netrin-1 induced an anti-apoptotic effect in B-ALL cells, implying that netrin-1 plays an oncogenic role in B-ALL. co-IP results showed that netrin-1 interacted with the receptor Unc5b in B-ALL cells. Interference with UNC5B was performed in B-ALL cells and abolished the antiapoptotic effects of netrin-1. Further western blotting was applied to detect the phosphorylation levels of key molecules in common signaling transduction pathways in B-ALL cells treated with recombinant netrin-1, and the FAK-MAPK signaling pathway was found to be activated. The anti-apoptotic effect of netrin-1 and FAK-MAPK phosphorylation was abrogated by UNC5B interference. FAK inhibitor treatment and ERK inhibitor treatment were applied and verified that the FAK-MAPK pathway may be downstream of Unc5b.

Conclusion

Taken together, our findings suggested that netrin-1 induced the anti-apoptotic effect of B-ALL cells through activation of the FAK-MAPK signaling pathway by binding to the receptor Unc5b. Video Abstract."xsd:string
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http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Huang L."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Liang S."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Yu J."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Xiao L."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Zeng X."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Zhu Y."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Zhang K."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"An X."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/author"Yao X."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/date"2022"xsd:gYear
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/name"Cell Commun Signal"xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/pages"122"xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/title"Netrin-1 induces the anti-apoptotic and pro-survival effects of B-ALL cells through the Unc5b-MAPK axis."xsd:string
http://purl.uniprot.org/citations/35974411http://purl.uniprot.org/core/volume"20"xsd:string
http://purl.uniprot.org/citations/35974411http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/35974411
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