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山东大学学报（医学版） ›› 2015, Vol. 53 ›› Issue (6): 33-38.doi: 10.6040/j.issn.1671-7554.0.2014.944

• 基础医学 • 上一篇    下一篇

硼替佐米耐药多发性骨髓瘤细胞基因表达谱分析

刘琼1, 蒲业迪2, 代广霞1, 马家乐1, 杨建霞1, 李丽珍1, 李颢1, 王鲁群1   

  1. 1. 山东大学齐鲁医院血液科, 山东 济南 250012;
    2. 天津市第一中心医院血液科, 天津 300192
  • 收稿日期:2014-12-11 修回日期:2015-02-28 出版日期:2015-06-10 发布日期:2015-06-10
  • 通讯作者: 王鲁群。 E-mail:wanglq@sdu.edu.cn E-mail:wanglq@sdu.edu.cn
  • 基金资助:
    山东省科技攻关计划(2008GG1002049);中国医师协会临床医学科研专项基金(20100123)

A microarray analysis of bortezomib-resistant gene expression in multiple myeloma

LIU Qiong1, PU Yedi2, DAI Guangxia1, MA Jiale1, YANG Jianxia1, LI Lizhen1, LI Hao1, WANG Luqun1   

  1. 1. Department of Hematology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China;
    2. Department of Hematology, Tianjin First Center Hospital, Tianjin 300192, China
  • Received:2014-12-11 Revised:2015-02-28 Online:2015-06-10 Published:2015-06-10

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摘要： 目的 应用基因芯片技术分析硼替佐米敏感细胞株KM3与耐药多发性骨髓瘤细胞株KM3/BTZ基因表达的差异性,探讨硼替佐米耐药相关基因及耐药发生机制。方法 采用Affymetrix U133 plus 2.0 全基因组表达谱芯片,分析KM3与KM3/BTZ之间的基因表达,采用RT-PCR法进一步检测基因表达的差异性,运用分子注释系统MAS3.0软件和已知耐药相关基因进行数据分析。结果 KM3/BTZ与KM3相比, 670个基因的表达具有差异性,表达差异10倍以上基因32个,主要涉及转录调控、信号传导通路等生物效应过程分子;HSPB2、ZNF及MS4A家族部分基因在KM3中低表达,在KM3/BTZ中强阳性表达;RT-PCR法检测显示,除JUN基因,其他7个基因(CA12、CYP1B1、EPB41L3、HSPB2、MS4A4A、SDPR、PAWR)与芯片检测表达差异结果相符。结论 在KM3与KM3/BTZ筛选中, ZNF、MS4A家族部分成员以及另外30个表达差异10倍以上的基因,均可能与多发性骨髓瘤硼替佐米耐药相关。全基因数据筛选和耐药相关基因具体分析,是探讨多发性骨髓瘤细胞耐药机制的理想方法之一。

关键词: 多发性骨髓瘤, 硼替佐米, 耐药, 基因芯片

Abstract: Objective To investigate genes related to bortezomib-resistance phenotype by analyzing different gene expression patterns with cDNA microarray and explore the mechanism of bortezomib-resistant myeloma. Methods Gene expression profiles of KM3/BTZ and KM3 cell lines were compared using Affymetrix U133 plus 2.0 oligonucleotide microarray. Specific differently-expressed genes were chosen for further verification by real-time RT-PCR. Relevant data were analyzed with molecular annotation system MAS3.0 software and compared with documented resistance genes. Results It was found that the KM3/BTZ cell line had 670 differently expressed genes as compared to KM3, of which 32 genes were increased or decreased by more than 10 folds. These 32 genes were involved in the regulation of transcription and signal transduction. Some genes of ZNF and MS4A family and HSPB2 were lowly expressed in KM3, but highly expressed in KM3/BTZ. Except for JUN, 7 genes (CA12, CYP1B1, EPB41L3, HSPB2, MS4A4A, SDPR, PAWR) were further verified using real-time RT-PCR and results were consistent with the microarray. Conclusion Some members of ZNF and MS4A family and another 30 genes whose differential expression is more than 10 folds between KM3 and KM3/BTZ may be related to bortezomib-resistance in multiple myeloma cells. Combination of filteringgenes and detailed analysis of documented resistance genes provides a potential approach to investigate the mechanism of drug resistance in multiple myeloma cells.

Key words: Multiple myeloma, Drug resistance, Bortezomib, cDNA microarray

中图分类号: 

  • R733.3
[1] Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibitionin human multiple myeloma cells[J]. Proc Natl Acad Sci USA, 2002, 99(22):14374-14379.
[2] Zheng B, Zhou R, Gong Y, et al. Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemia cell lines[J]. Biochemical Int J Lab Hematol, 2012, 34(3):237-247.
[3] 蒲业迪, 李丽珍, 马道新, 等. 硼替佐米耐药多发性骨髓瘤细胞株KM3/BTZ的建立[J]. 山东大学学报:医学版, 2013, 51(2):33-36. PU Yedi, LI Lizhen, MA Daoxin, et al. Establishment of a bortezomib-resistant cell line KM3/BTZ of human multiple myeloma[J]. Journal of Shandong University:Health Sciences, 2013, 51(2):33-36.
[4] 李荣, 侯建. 新药时代造血干细胞移植治疗多发性骨髓瘤若干问题探讨[J]. 中国实用内科杂志, 2014, 34(2):115-117. LI Rong, HOU Jian. Several issues concerning hematopoietic stem cell transplantation in treatment of multiple myeloma in the new drugarea[J]. Chinese Journal of Practical Internal Medicine, 2014, 34(2):115-117.
[5] Palumbo A, Ambrosini MT, Benevolo G, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma[J]. Blood, 2007, 109(7):2767-2772.
[6] Berenson JR, Yang HH, Sadler K, et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma[J]. J Clin Oncol, 2006, 24(6):937-944.
[7] Richardsom PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma[J]. Blood, 2014, 123(10):1461-1469.
[8] Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells[J]. Cancer Res, 2003, 63(69):6174-6177.
[9] Oerlemans R, Franke NE, Assaraf YG, et al. Molecular basis of bortezomib resistance:proteasome subunit beta5(PSMB5) gene mutation and overexpression of PSMB5 protein[J]. Blood, 2008, 112(6):2489-2499.
[10] Carrasco DR, Sukhdeo K, Protopopova M, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis[J]. Cancer Cell, 2007, 411(4):349-360.
[11] Teru Hideshima, Klaus Podar, Dharminder Chauhan, et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells[J]. Oncogene, 2004, 23(54):8766-8776.
[12] Wang BD, Kline CL, Pastor DM, et al. Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NF kappaB and microRNA network[J]. Mol Cancer, 2010, 430(9):1186-1476.
[13] Takagi Y, Nozaki K, Sugino T, et al. Phosphorylation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase after transient forebrain ischemia in mice[J]. Neurosci Lett, 2000, 294(2):117-120.
[14] Shringarpure R, Catley L, Bhole D, et al.Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib[J]. Br J Haematol, 2006, 134(2):145-156.
[15] Hoovers J, Mannens M, John R, et al. High-resolution localization of 69 potential human zinc finger protein genes:A number are clustered[J]. Genomics, 1992, 12(2):254-263.
[16] Huebner K, Druck T, Croce C, et al. Twenty-seven nonoverlapping zinc finger cDNAs from human T cells map to nine different chromosomes with apparent clustering[J]. Am J Hum Genet, 1991, 48(4):726-740.
[17] Duan Z, Choy E, Harmon D, et al. ZNF93 increases resistance to ET-743 (Trabectedin; Yondelis) and PM00104 (Zalypsis) in human cancer cell lines[J]. PLoS One, 2009, 6(9):728-732.
[18] Liang Y, Buckley TR, Tu L, et al. Structural organization of the human MS4A gene cluster on Chromosome 11q12[J]. Immunogenetics, 2001, 53(5):357-368.
[19] Liang Y, Tedder TF. Identification of a CD20-, FcepsilonRIbeta-, and HTm4 related gene family:sixteen new MS4A family members expressed in human and mouse[J]. Genomics, 2001, 72(2):119-127.
[20] Kutok JL, Yang X, Folkerth R, et al. Characterization of the expression of HTm4 (MS4A3), a cell cycle regulator, in human peripheral blood cells and normal and malignant tissues[J]. J Cell Mol Med, 2011, 15(1):86-93.
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