弥漫大B细胞淋巴瘤微小RNA的异常表达及核心基因筛选

doi:10.3969/j.issn.1004-616x.2022.04.003

摘要/Abstract

摘要： 目的：寻找弥漫大B细胞淋巴瘤(DLBCL)中异常表达的微小RNA (miRNA)及其核心基因(hub基因)，以期为DLBCL的发病机制研究提供新的靶标。方法：从GEO数据库中选择GSE117063数据集，该数据集包括17例DLBCL患者和14例健康对照的血浆样本，借助GEO2R工具筛选差异表达的miRNA，之后在miRTarBase网站预测miRNA的靶基因，使用DAVID网站对靶基因进行GO基因功能和KEGG通路富集分析。此外，通过蛋白质相互作用(PPI)网络筛选hub基因，构建miRNA-hub基因调控网络。最后，采用GEPIA数据库验证hub基因在DLBCL和正常组织中的表达。结果：与健康对照相比，hsa-miRNA-326在DLBCL样本中表达上调，hsa-miRNA-375表达下调，其调控的靶基因主要富集在HTLV-I感染通路和PI3K/AKT信号通路及基质中的蛋白多糖等通路，7个hub基因(AKT1、CCND1、ERBB2、TP53、MYC、CTNNB1和HSP90AA1)经验证在DLBCL中存在异常表达。结论：miRNA-326和miRNA-375及其靶基因可能在DLBCL的发病机制中发挥重要作用。

关键词: 弥漫大B细胞淋巴瘤, 微小RNA, 核心基因, 发病机制

Abstract: OBJECTIVE: To identify differentially expressed microRNA(miRNA) and hub gene associated with diffuse large B-cell lymphoma (DLBCL) and to find novel targets for mechanistic studies of DLBCL. METHODS: Dataset GSE117063 was chosen from the Gene Expression Omnibus (GEO) database, which included plasma samples from 17 DLBCL patients and 14 healthy individuals,and DE-miRNAs were selected by GEO2R. The potential target genes were predicted by miRTarBase. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were implemented using Database for Annotation, Visualization and Integrated Discovery (DAVID). Additionally,hub genes were screened by the Protein-Protein Interaction (PPI) network and miRNA-gene regulatory network was constructed. Finally,differential expressions of hub genes were verified by Gene Expression Profiling Interactive Analysis (GEPIA). RESULTS: The up-regulation of hsa-miRNA-326 and down-regulation of hsa-miRNA-375 were significantly and differentially expressed in DLBCL and healthy tissues. The target genes mainly participated in positive regulation of cell proliferation and enriched in HTLV-I infection,PI3K-Akt signaling pathway,proteoglycans in cancer and so on. Seven regulated hub genes (AKT1,CCND1,ERBB2,TP53,MYC,CTNNB1 and HSP90AA1) were verified to be differentially expressed in DLBCL. CONCLUSION: The up-regulated miRNA-326 and down-regulaed miRNA-375 and target genes might play important roles in pathogenesis of DLBCL.

Key words: diffuse large B-cell lymphoma, microRNA, hub gene, pathogenesis

中图分类号:

R733.4

杨柳青, 杨美虹, 刘波, 张倩, 李新霞. 弥漫大B细胞淋巴瘤微小RNA的异常表达及核心基因筛选[J]. 癌变·畸变·突变, 2022, 34(4): 262-268.

YANG Liuqing, YANG Meihong, LIU Bo, ZHANG Qian, LI Xinxia. Identification of differentially expressed microRNA and hub gene in diffuse large B-cell lymphoma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(4): 262-268.

参考文献

[1] MARTELLI M, FERRERI A J M, AGOSTINELLI C, et al.Diffuse large B-cell lymphoma[J].Crit Rev Oncol, 2013, 87(2):146-171.
[2] ZHANG J, GRUBOR V, LOVE C L, et al.Genetic heterogeneity of diffuse large B-cell lymphoma[J].PNAS, 2013, 110(4):1398-1403.
[3] KYROLLOS D G, REID B, DICK K, et al.RPmirDIP:Reciprocal perspective improves miRNA targeting prediction[J].Sci Rep, 2020, 10(1):11770.
[4] OHMOTO A, FUJI S.Histological transformation in malignant lymphoma:a possible role of PET/CT and circulating tumor DNA as noninvasive diagnostic tools[J].Expert Rev Hematol, 2020, 13(1):23-30.
[5] CHANTADA G, LAM C G, HOWARD S C.Optimizing outcomes for children with non-Hodgkin lymphoma in lowand middle-income countries by early correct diagnosis, reducing toxic death and preventing abandonment[J].Br J Haematol, 2019, 185(6):1125-1135.
[6] TANG Z F, LI C W, KANG B X, et al.GEPIA:a web server for cancer and normal gene expression profiling and interactive analyses[J].Nucleic Acids Res, 2017, 45(1):98-102.
[7] KROH E M, PARKIN R K, MITCHELL P S, et al.Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR)[J].Methods, 2010, 50(4):298-301.
[8] HARHAJ E W, GIAM C Z.NF-κB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma[J].FEBS J, 2018, 285(18):3324-3336.
[9] RIGOGLIO N N, RABELO A C S, BORGHESI J, et al.The tumor microenvironment:focus on extracellular matrix[J].Adv Exp Med Biol, 2020, 1245:1-38.
[10] SIMON DAVIS D A, PARISH C R.Heparan sulfate:a ubiquitous glycosaminoglycan with multiple roles in immunity[J].Front Immunol, 2013, 4:470.
[11] GAO H X, LI S J, NIU J, et al.TCL1 as a hub protein associated with the PI3K/AKT signaling pathway in diffuse large B-cell lymphoma based on proteomics methods[J].Pathol Res Pract, 2020, 216(2):152799.
[12] WANG W G, CUI W L, WANG L, et al.Loss of B-cell receptor expression defines a subset of diffuse large B-cell lymphoma characterized by silent BCR/PI3K/AKT signaling and a germinal center phenotype displaying low-risk clinicopathologic features[J].Am J Surg Pathol, 2015, 39(7):902-911.
[13] WANG J F, XU-MONETTE Z Y, JABBAR K J, et al.AKT hyperactivation and the potential of AKT-targeted therapy in diffuse large B-cell lymphoma[J].Am J Pathol, 2017, 187(8):1700-1716.
[14] PEIRIS M N, MEYER A N, NELSON K N, et al.Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation[J].Haematologica, 2020, 105(5):1262-1273.
[15] MUSGROVE E A, CALDON C E, BARRACLOUGH J, et al.Cyclin D as a therapeutic target in cancer[J].Nat Rev Cancer, 2011, 11(8):558-572.
[16] GAVIRAGHI M, RABELLINO A, ANDOLFO A, et al.Direct stimulation of ERBB₂ highlights a novel cytostatic signaling pathway driven by the receptor Thr 701 phosphorylation[J].Sci Rep, 2020, 10(1):16906.
[17] ROSENWALD A, BENS S, ADVANI R, et al.Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma:a study by the Lunenburg lymphoma biomarker consortium[J].J Clin Oncol, 2019, 37(35):3359-3368.
[18] LI Y K, ZHANG F Q, YANG D H.Comprehensive assessment and meta-analysis of the association between CTNNB1 polymorphisms and cancer risk[J].Biosci Rep, 2017, 37(6):BSR20171121.
[19] KIM S, JEONG S.Mutation hotspots in the β-catenin gene:lessons from the human cancer genome databases[J].Mol Cells, 2019, 42(1):8-16.
[20] VOROPAEVA E N, POSPELOVA T I, VOEVODA M I, et al.Clinical aspects of TP53 gene inactivation in diffuse large Bcell lymphoma[J].BMC Med Genomics, 2019, 12(Suppl 2):35.
[21] WANG R, XU J L, XU J, et al.miR-326/Sp1/KLF3:a novel regulatory axis in lung cancer progression[J].Cell Prolif, 2019, 52(2):e12551.
[22] PAN S M, LIU Y Q, LIU Q Q, et al.HOTAIR/miR-326/FUT6 axis facilitates colorectal cancer progression through regulating fucosylation of CD44 via PI3K/AKT/mTOR pathway[J].Biochim Biophys Acta Mol Cell Res, 2019, 1866(5):750-760.
[23] LU Y Y, DENG X B, XIAO G H, et al.circ_0001730 promotes proliferation and invasion via the miR-326/Wnt7B axis in glioma cells[J].Epigenomics, 2019, 11(11):1335-1352.
[24] CHEN X X, XU M, XU X N, et al.METTL14 suppresses CRC progression via regulating N6-methyladenosine-dependent primary miR-375 processing[J].Mol Ther, 2020, 28(2):599-612.
[25] TANG W, LI G S, LI J D, et al.The role of upregulated miR-375 expression in breast cancer:an in vitro and in silico study[J].Pathol Res Pract, 2020, 216(1):152754.
[26] GAN T Q, CHEN W J, QIN H, et al.Clinical value and prospective pathway signaling of microRNA-375 in lung adenocarcinoma:a study based on the cancer genome atlas (TCGA), gene expression omnibus (GEO) and bioinformatics analysis[J].Med Sci Monit, 2017, 23:2453-2464.
[27] KOUTOVA L, STERBOVA M, PAZOURKOVA E, et al.The impact of standard chemotherapy on miRNA signature in plasma in AML patients[J].Leuk Res, 2015, 39(12):1389-1395.
[28] BI L X, ZHOU B, LI H Y, et al.A novel miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry contributes to leukemogenesis in acute myeloid leukemia[J].BMC Cancer, 2018, 18(1):182.