Rs۷۶۶۳۸۸۰۷ hinder PAG۱'s ability to promote CSK activation in DLBLC patients

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma, accounting for a significant portion of lymphoma cases worldwide. Despite advances in treatment, the prognosis for DLBCL patients remains variable, highlighting the need for a better understanding of the molecular mechanisms underlying this cancer. PAG۱ (Phosphoprotein Associated with Glycosphingolipid-enriched Microdomains ۱) Negatively regulates TCR (T-cell antigen receptor) ,mediated signaling in T-cells and FCER۱ (high affinity immunoglobulin epsilon receptor) and mediated signaling in mast cells. It also Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. It may be involved in cell adhesion signaling. Methods: The GSE۱۴۵۸۴۷ dataset from the Gene Expression Omnibus (GEO) database was utilized to analyze PAG۱ expression levels in DLBCL samples. PAG۱ was selected form significant low expressions. Additionally, the GEPIA۲ and ENCORI platforms were used to conduct expression profile, survival, and correlation analyses. Gene ontology and biological pathway analyses were performed using the Enricher database. The Reactome and KEGG databases were employed to explore the signaling pathways potentially influenced by PAG۱ In an effort to identify potential functional variants within the PAG۱ gene, SNPs were analyzed using bioinformatics tools such as SIFT, miRNASNP, and dbSNP. One coding sequence SNP, rs۷۶۶۳۸۸۰۷, was identified and further investigated. Protein-protein interactions involving PAG۱ were analyzed using the STRING database, while miRwalk and LncRRIsearch were utilized to study the interactions between PAG۱ and its related miRNAs and lncRNAs, respectively. Finally, the Hope database was employed to assess the potential impact of the identified SNP (rs۷۶۶۳۸۸۰۷) on the PAG۱ protein structure and function Results: Based on microarray analysis, PAG۱ has significant lower expression in DLBCL patiants( logFC: -۵.۳۸, adj.P.Val: ۱.۲۹E-۱۹ ) compared to control samples. PAG۱ Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. HOPE dataset has shown the mutation of a Arginine into a Tryptophan at position ۳۰۲ had The effect of mutant residue is bigger than the wild-type residue, the wild-type residue charge was POSITIVE, the mutant residue charge is NEUTRAL and the mutant residue is more hydrophobic than the wild-type residue. It has demonstrated in Pr-Pr interaction analysis that PAG۱ has significant interaction with LCK. Hsa-miR-۶۷۶۹b-۳p has a significant interaction with PAG۱ mRNA in the ۳'UTR. TSIX lncRNA has shown a significant interaction with PAG۱ mRNA. Conclusion: The findings of this study suggest that the PAG۱ gene exhibits a significant decrease in expression in DLBCL, potentially contributing to the pathogenesis of this cancer. The mutation might hinder PAG۱'s ability to promote CSK activation or its recruitment to lipid rafts, which could result in insufficient inhibition of LCK. This could lead to unchecked LCK activity, affecting downstream signaling pathways. LCK is involved in the initiation of BCR signaling. Enhanced LCK activity can lead to continuous activation of the BCR pathway, promoting cell proliferation and survival. The possible effect of this SNP has not been studied yet.

کلیدواژه ها:

PAG۱ ، DLBLC ، CSK