Differences between Primary Central Nervous System Diffuse Large B-Cell Lymphoma and Intra-Lymph Node Diffuse Large B-Cell Lymphoma Based on Proteomic Research

Background:

Primary central nervous system lymphoma(PCNSL) is a rare extranodal lymphoma with limited lesions. About 95% or more of the patients have a pathologic staging of diffuse large B-cell lymphoma(DLBCL), which is characterized by highly aggressive, rapid progression, and poor prognosis, and is distinctly different from intra-lymph node DLBCL with respect to site of onset, clinical manifestations, and treatment.Currently, high-dose MTX-based chemotherapy is the main treatment strategy for PCNSL, but most patients suffer from treatment resistance and relapse, and the 5-year overall survival rate is only 30%. Because of the low prevalence of PCNSL and the difficulty in obtaining samples, studies at the molecular biology level are very limited, so proteomics-based studies are necessary.In exploring the differences between the two, proteomics technology can identify and quantitatively analyze the entire range of proteins, and by screening meaningful differential proteins and analyzing the signaling pathways in which they are involved, it can reveal the potential pathogenesis and therapeutic approaches to diseases. Therefore, in-depth understanding of the protein expression profile of PCNSL, clarifying the pathogenesis, and searching for potential therapeutic targets are crucial for improving patient survival.

Purpose:

Based on proteomics technology, this project expects to discover the differences in protein expression between primary central nervous system diffuse large B-cell lymphoma(PCNS DLBCL) and intra-lymph node DLBCL, and to search for meaningful differential proteins that could lead to the discovery of potential therapeutic targets or biomarkers.

Methods:

Surgical resection specimens of five patients with PCNS DLBCL were selected as group A, and biopsy pathology specimens of five patients with intra-lymph node DLBCL were selected as group B. The samples were subjected to quantitative proteomic studies through the organic combination of a series of cutting-edge technologies such as protein extraction, enzymatic digestion, liquid chromatography-mass spectrometry tandem analysis, and bioinformatic analysis. Finally, bioinformatic analysis was performed to analyze the differential proteins and the signaling pathways they are involved in, to explore the pathogenesis of both, and to find potential therapeutic targets or biomarkers.

Results:

Good variability between the comparison groups and good intra-group reproducibility within groups. When p<0.05, a change in differential expression level exceeding 1.5 is considered a significant upregulation threshold, and a change level less than 1/1.5 is considered a significant downregulation threshold. The top five differential proteins with significant difference up-regulated between A/B groups were TUBA8, CKB, S100B, TUBB2A, SLC1A3, and the top five differential proteins with significant difference down-regulated were were EFEMP1, AOC3, FBLN5, LOXL1, and ACTA2, respectively. Functional enrichment analysis of the differentially expressed proteins (Fc>1.5,p<0.05) between A/B groups revealed gap junctions, a signaling pathway whose activation has been found to promote tumor cell growth and brain metastasis of solid malignant tumors, such as lung and breast cancers, in previous studies. Among them, TUBA8 and TUBB2A proteins, which are significantly differentially up-regulated in the top 5, HRAS and GNAI1 up-regulated proteins, which are in the pivotal position in the protein interaction network diagram, are involved in the process of this signaling pathway. Increased expression of these proteins can promote the activation of the gap junction pathway, thus promoting tumor cell growth and central involvement.

Conclusion:

PCNS DLBCL is significantly different from intra-lymph node DLBCL at the proteomic level.According to the function enrichment results of differentially expressed proteins, we found that the gap junction pathway is closely related to the promotion of tumor growth and brain metastasis, of which TUBA8, TUBB2A, HRAS, GNAI1 are the key proteins, and it is expected to develop new drugs based on the relevant targets to reduce the expression of the relevant proteins, and thus inhibit the activation of the gap junction pathway, which will provide a new direction for the treatment of PCNSL. Immunohistochemical testing for correlation validation is in progress.

No relevant conflicts of interest to declare.