Investigating critical genes and gene interaction networks that mediate cyclophosphamide sensitivity in chronic myelogenous leukemia.
Investigating critical genes and gene interaction networks that mediate cyclophosphamide sensitivity in chronic myelogenous leukemia.
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DOI：
10.3892/mmr.2017.6636
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发表时间：
2017-07
影响因子：
3.4
通讯作者：
Yue W
中科院分区：
文献类型：
--
作者：
He X;Deng Y;Yue W
耐药性是慢性粒细胞白血病（CML）治疗的障碍，是治疗失败或疾病进展的常见原因。然而，环磷酰胺耐药的潜在机制仍然不清楚。在本研究中，芯片数据有关环磷酰胺敏感和耐药的慢性粒细胞白血病细胞系进行了分析。在这两组之间共鉴定出258个差异表达基因（DEG），其中139个DEG上调，119个下调。还鉴定了与环磷酰胺抗性相关的几个候选基因。随后使用基因本体和京都基因和基因组百科全书（KEGG）富集途径分析对这些DEG进行分类。共有487个生物过程和17个KEGG途径被发现富集。此外，建立了一个相互作用网络，以确定调控环磷酰胺抗性的核心基因。STAT 5A、FYN原癌基因、Src家族酪氨酸激酶和脾相关酪氨酸激酶是CML细胞中多种丰富的生物学过程和信号通路的枢纽基因，参与了CML细胞对环磷酰胺的敏感性。逆转录-定量聚合酶链反应（RT-PCR）检测了5种DEG在两种CML细胞系（K-562和KU 812）中的表达。此外，选择性敲低STAT 5A和S100钙结合蛋白A4（S100 A4）恢复了K-562细胞对环磷酰胺的敏感性，表明它们参与了耐药性。本研究确定了几个可能导致环磷酰胺耐药的基因和途径，并证实了STAT 5A和S100 A4参与耐药。这些结果使我们能够更好地理解CML细胞耐药的机制。
Drug resistance is an obstacle in the treatment of chronic myelogenous leukemia (CML), and is a common reason for treatment failure or disease progression. However, the underlying mechanisms of cyclophosphamide resistance remain poorly defined. In the present study, microarray data concerning cyclophosphamide-sensitive and -resistant chronic myelogenous leukemia cell lines were analyzed. A total of 258 differentially-expressed genes (DEGs) were identified between these two groups, from which 139 DEGs were upregulated and 119 were downregulated. Several candidate genes that were associated with cyclophosphamide resistance were also identified. These DEGs were subsequently classified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. A total of 487 biological processes and 17 KEGG pathways were revealed to be enriched. Furthermore, an interaction network was established to identify the core genes that regulated cyclophosphamide resistance. Signal transducer and activator of transcription 5A (STAT5A), FYN proto-oncogene, Src family tyrosine kinase and spleen associated tyrosine kinase were revealed to be the hub genes in multiple enriched biological processes and signaling pathways, indicating that these were involved in mediating cyclophosphamide sensitivity in CML cells. The expression levels of 5 DEGs were also confirmed in two human CML cell lines (K-562 and KU812) by reverse transcription-quantitative polymerase chain reaction. Furthermore, selective knockdown of STAT5A and S100 calcium binding protein A4 (S100A4) recovered cyclophosphamide sensitivity in K-562 cells, suggesting their involvement in drug resistance. The present study identified several potential genes and pathways contributing to cyclophosphamide resistance, and confirmed the involvement of STAT5A and S100A4 in drug resistance. These results enable improved understanding of the mechanisms underlying drug resistance in CML cells.