|Table of Contents|

Screening key genes of diffuse large B-cell lymphoma with c-MYC/Bcl-2 translocation based on WGCNA analysis

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 01
Page:
96-103
Research Field:
Publishing date:

Info

Title:
Screening key genes of diffuse large B-cell lymphoma with c-MYC/Bcl-2 translocation based on WGCNA analysis
Author(s):
LI Hongyi1; 2; GUO Bo2; ZHANG Haojun2; 3; CHEN Haoran2; 3; HOU Chuandong1; 2; LU Xuechun1; 2; 3
1.Medical School of Chinese PLA,Beijing 100853,China；2.Department of Hematology,the Second Medical Center of Chinese PLA General Hospital,Beijing 100853,China；3.Shanxi Medical University,Shanxi Taiyuan 030001,China.
Keywords:
high-grade B-cell lymphoma; diffuse large B-cell lymphoma; gene rearrangement; medical bioinformatics; biomarker
PACS:
R733.4
DOI:
10.3969/j.issn.1672-4992.2024.01.017
Abstract:
Objective:To identify the potential high-risk genes and pathogenic pathways in DLBCL with c-MYC/Bcl-2 translocation,and to establish a theoretical foundation for understanding the pathogenesis of this specific lymphoma subtype.Methods:GSE44164 and GSE43677 datasets were acquired from the Gene Expression Omnibus (GEO) database.The experimental group consisted of DLBCL cases with c-MYC/Bcl-2 translocation,while germinal center B cells were utilized as the control group.Differential expression analysis,gene co-expression change analysis,GO enrichment analysis,and KEGG pathway enrichment analysis of the mRNA transcriptome data were conducted using the R programming language,with the limma,WGCNA,and clusterProfiler packages.Protein interaction network analysis of differentially expressed genes(DEGs) was performed using STRING database,and the core genes were identified via Cytoscape software,employing CytoHubba and CytoNca plug-ins.The mRNA transcriptomes of IM-9 and DOHH-2 cell lines were sequenced using The Next Generation Sequencing.The core genes were analyzed by paired sample t test based on Read count values,and genes exhibiting statistically significant P-values were identified as the core disease-associated genes.Furthermore,a subset of key genes was selected for validation through Western Blot.Results:A total of 835 DEGs were obtained by differential analysis,and WGCNA obtained a module that was highly correlated with c-MYC/Bcl-2 translocated DLBCL (turquoise module,cor=0.86,P-value<0.05).GO enrichment analysis showed that a total of 1 437 biological process BP,123 cell component CC and 147 molecular function-related MF were enriched.KEGG enrichment identified 72 related pathways,which were mainly related to ECM receptor interaction,B cell receptor signaling pathway and PI3K-Akt signaling pathway.A total of 284 interacting proteins were obtained from the protein interaction network of STRING database,which were further screened by Cytoscape software.The Next Generation Sequencing and Western Blot verified that COL1A1,COL3A1,COL1A2,MMP2,COL5A1,COL5A2,COL4A2,TIMP1,MMP9,POSTN,BGN,DCN and LUM were the core genes of this type of lymphoma,which affected the survival,invasion and migration of this type of lymphoma cells.Conclusion:To investigate the core genes associated with the pathogenesis,invasion,and migration of c-MYC/Bcl-2 translocated DLBCL cells through the integration of bioinformatics and fundamental experimental methods,with the ultimate goal of laying a theoretical foundation for deeper insights into the mechanisms underlying the initiation and progression of this specific lymphoma subtype,as well as the identification of potential targeted therapeutic agents.

References:

［1］ SUSANIBAR-ADANIYA S,BARTA SK.2021 update on diffuse large B cell lymphoma:a review of current data and potential applications on risk stratification and management ［J］.Am J Hematol,2021,96(5):617-629.
［2］ SWERDLOW SH,CAMPO E,PILERI SA,et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms ［J］.Blood,2016,127(20):2375-2390.
［3］ DAVIES A.Double-hit lymphoma:so what［J］.Hematol Oncol,2019,37(Suppl 1):19-23.
［4］ RITCHIE ME,PHIPSON B,WU D,et al.Limma powers differential expression analyses for RNA-sequencing and microarray studies ［J］.Nucleic Acids Res,2015,43(7):e47.
［5］ LANGFELDER P,HORVATH S.WGCNA:an R package for weighted correlation network analysis ［J］.BMC Bioinformatics,2008,9:559.
［6］ 李经蕾,侯炜.基于TCGA和Oncomine数据库分析肺腺癌预后基因表达及临床意义［J］.现代肿瘤医学,2022,30(05):819-823. LI JL,HOU W.Analysis of prognostic gene expression of lung adenocarcinoma based on TCGA and oncomine databases and its clinical significance［J］.Modern Oncology,2022,30(05):819-823.
［7］ WANG F,WANG B,LONG J,et al.Identification of candidate target genes for endometrial cancer,such as ANO1,using weighted gene co-expression network analysis ［J］.Exp Ther Med,2019,17(1):298-306.
［8］ FULLER TF,GHAZALPOUR A,ATEN JE,et al.Weighted gene coexpression network analysis strategies applied to mouse weight ［J］.Mamm Genome,2007,18(6-7):463-472.
［9］ XIE W,HUANG J,LIU Y,et al.Exploring potential new floral organ morphogenesis genes of arabidopsisthaliana using systems biology approach ［J］.Front Plant Sci,2015,6:829.
［10］ LUO W,BROUWER C.Pathview:an R/Bioconductor package for pathway-based data integration and visualization ［J］.Bioinformatics,2013,29(14):1830-1831.
［11］ CHIN CH,CHEN SH,WU HH,et al.CytoHubba:identifying hub objects and sub-networks from complex interactome ［J］.BMC Syst Biol,2014,8(Suppl 4):S11.
［12］ TANG Y,LI M,WANG J,et al.CytoNCA:a cytoscape plugin for centrality analysis and evaluation of protein interaction networks ［J］.Biosystems,2015,127:67-72.
［13］ RIEDELL PA,SMITH SM.Double hit and double expressors in lymphoma:definition and treatment ［J］.Cancer,2018,124(24):4622-4632.
［14］ BASU A.The interplay between apoptosis and cellular senescence:Bcl-2 family proteins as targets for cancer therapy［J］.Pharmacol Ther,2022,230:107943.
［15］ FAIRLIE WD,LEE EF.Co-operativity between MYC and Bcl-2 pro-survival proteins in cancer［J］.Int J Mol Sci,2021,22(6):2841.
［16］ NG HH,SHEN M,SAMUEL CS,et al.Relaxin and extracellular matrix remodeling:mechanisms and signaling pathways ［J］.Mol Cell Endocrinol,2019,487:59-65.
［17］QURESHI S,KHANDELWAL R,MADHAVI M,et al.A multi-target drug designing for BTK,MMP9,proteasome and TAK1 for the clinical treatment of mantle cell lymphoma ［J］.Curr Top Med Chem,2021,21(9):790-818.
［18］ LIU W,FU X,LI R.CNN1 regulates the DKK1/Wnt/beta-catenin/c-myc signaling pathway by activating TIMP2 to inhibit the invasion,migration and EMT of lung squamous cell carcinoma cells ［J］.Exp Ther Med,2021,22(2):855.
［19］ SONG B,LI XF,YAO Y,et al.BMP9 inhibits the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis via the PI3K/AKT signaling pathway ［J］.Int Immunopharmacol,2019,74:105685.
［20］ ZHU XW,WANG J,ZHU MX,et al.MicroRNA-506 inhibits the proliferation and invasion of mantle cell lymphoma cells by targeting B7H3 ［J］.Biochem Biophys Res Commun,2019,508(4):1067-1073.
［21］ LI X,SUN X,KAN C,et al.COL1A1:a novel oncogenic gene and therapeutic target in malignancies ［J］.Pathol Res Pract,2022,236:154013.
［22］ WU Y,XU Y.Integrated bioinformatics analysis of expression and gene regulation network of COL12A1 in colorectal cancer ［J］.Cancer Med,2020,9(13):4743-4755.
［23］ CIOROIANU AI,STINGA PI,STICLARU L,et al.Tumor microenvironment in diffuse large B-cell lymphoma:role and prognosis ［J］.Anal Cell Pathol (Amst),2019,2019:8586354.
［24］ PENG J,FU B,FU G,et al.Effect of NPM1 type B mutation on the proliferation,invasion and chemosensitivity of THP-1 leukemia cells ［J］.Pharmazie,2017,72(10):608-613.
［25］ WANG H,LIU Z,ZHANG G.FBN1 promotes DLBCL cell migration by activating the Wnt/beta-catenin signaling pathway and regulating TIMP1 ［J］.Am J Transl Res,2020,12(11):7340-7353.
［26］ BORBELY AU,DAHER S,ISHIGAI MM,et al.Decorin and biglycan immunolocalization in non-villous structures of healthy and pathological human placentas ［J］.Histopathology,2014,64(5):616-625.
［27］ BERDIAKI A,GIATAGANA EM,TZANAKAKIS G,et al.The landscape of small leucine-rich proteoglycan impact on cancer pathogenesis with a focus on biglycan and lumican ［J］.Cancers (Basel),2023,15(14):3549.
［28］ SUBBARAYAN K,SELIGER B.Tumor-dependent effects of proteoglycans and various glycosaminoglycan synthesizing enzymes and sulfotransferases on patients' outcome ［J］.Curr Cancer Drug Targets,2019,19(3):210-221.
［29］ MAISHI N,HIDA K.Tumor endothelial cells accelerate tumor metastasis ［J］.Cancer Sci,2017,108(10):1921-1926.
［30］ JARVINEN TA,PRINCE S.Decorin:a growth factor antagonist for tumor growth inhibition ［J］.Biomed Res Int,2015,2015:654765.
［31］ APPUNNI S,ANAND V,KHANDELWAL M,et al.Altered expression of small leucine-rich proteoglycans (decorin,biglycan and lumican):Plausible diagnostic marker in urothelial carcinoma of bladder ［J］.Tumour Biol,2017,39(5):1010428317699112.
［32］ WASIK A,RATAJCZAK-WIELGOMAS K,BADZINSKI A,et al.The role of periostin in angiogenesis and lymphangiogenesis in tumors ［J］.Cancers (Basel),2022，14(17):4225.
［33］ HAVRANEK O,XU J,KOHRER S,et al.Tonic B-cell receptor signaling in diffuse large B-cell lymphoma ［J］.Blood,2017,130(8):995-1006.
［34］ XU W,BERNING P,LENZ G.Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma ［J］.Blood,2021,138(13):1110-1119.

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Last Update: 2023-11-30