Zheng Zhihong, Liu Tingbo, Zheng Jing, Hu Jianda
Department of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China.
Onco Targets Ther. 2017 Mar 1;10:1327-1334. doi: 10.2147/OTT.S130742. eCollection 2017.
Carfilzomib is a Food and Drug Administration-approved selective proteasome inhibitor for patients with multiple myeloma (MM). However, recent studies indicate that MM cells still develop resistance to carfilzomib, and the molecular mechanisms associated with carfilzomib resistance have not been studied in detail. In this study, to better understand its potential resistant effect and its underlying mechanisms in MM, microarray gene expression profile associated with carfilzomib-resistant KMS-11 and its parental cell line was downloaded from Gene Expression Omnibus database. Raw fluorescent signals were normalized and differently expressed genes were identified using Significance Analysis of Microarrays method. Genetic interaction network was expanded using String, a biomolecular interaction network JAVA platform. Meanwhile, molecular function, biological process and signaling pathway enrichment analysis were performed based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Totally, 27 upregulated and 36 downregulated genes were identified and a genetic interaction network associated with the resistant effect was expanded basing on String, which consisted of 100 nodes and 249 edges. In addition, signaling pathway enrichment analysis indicated that cytokine-cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways were aberrant in carfilzomib-resistant KMS-11 cells. Thus, in this study, we demonstrated that carfilzomib potentially conferred drug resistance to KMS-11 cells by cytokine-cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways, which may provide some potential molecular therapeutic targets for drug combination therapy against carfilzomib resistance.
卡非佐米是一种经美国食品药品监督管理局批准用于治疗多发性骨髓瘤（MM）患者的选择性蛋白酶体抑制剂。然而，最近的研究表明，MM细胞对卡非佐米仍会产生耐药性，且与卡非佐米耐药相关的分子机制尚未得到详细研究。在本研究中，为了更好地了解其在MM中的潜在耐药作用及其潜在机制，从基因表达综合数据库下载了与卡非佐米耐药的KMS-11及其亲本细胞系相关的微阵列基因表达谱。对原始荧光信号进行归一化处理，并使用微阵列显著性分析方法鉴定差异表达基因。利用生物分子相互作用网络JAVA平台String扩展遗传相互作用网络。同时，基于基因本体论和京都基因与基因组百科全书进行分子功能、生物学过程和信号通路富集分析。总共鉴定出27个上调基因和36个下调基因，并基于String扩展了一个与耐药作用相关的遗传相互作用网络，该网络由100个节点和249条边组成。此外，信号通路富集分析表明，细胞因子-细胞因子受体相互作用、自噬、表皮生长因子受体（ErbB）信号通路、癌症中的微小RNA以及脂肪酸代谢通路在卡非佐米耐药的KMS-11细胞中存在异常。因此，在本研究中，我们证明卡非佐米可能通过细胞因子-细胞因子受体相互作用、自噬、ErbB信号通路、癌症中的微小RNA以及脂肪酸代谢通路赋予KMS-11细胞耐药性，这可能为针对卡非佐米耐药的联合药物治疗提供一些潜在的分子治疗靶点。
