Zhang Hai-Hong, Zhang Zhi-Yi, Che Chun-Li, Mei Yi-Fang, Shi Yu-Zhi
Department of rheumatism and immunology, First Clinical Medical College affiliated to Harbin Medical University Harbin, China.
Int J Clin Exp Pathol. 2013 Aug 15;6(9):1734-46. eCollection 2013.
Gemcitabine is one of the most widely used drugs for the treatment of advanced Non-small cell lung cancer (NSCLC), but modest objective response rate of patients to gemcitabine makes it necessary to identify novel biomarkers for patients who can benefit from gemcitabine-based therapy and to improve the effect of clinical therapy. In this work, 3 NSCLC cell lines displaying different sensitivities to gemcitabine were applied for mRNA and microRNA (miR) expression chips to figure out the biomarkers for gemcitabine sensitivity. Genes whose expression increased dramatically in sensitive cell lines were mainly enriched in cell adhesion (NRP2, CXCR3, CDK5R1, IL32 and CDH2) and secretory granule (SLC11A1, GP5, CD36 and IGF1), while genes with significantly upregulated expression in resistant cell line were mainly clustered in methylation modification (HIST1H2BF, RAB23 and TP53) and oxidoreductase (TP53I3, CYP27B1 and SOD3). The most intriguing is the activation of Wnt/β-catenin signaling in gemcitabine resistant NSCLC cell lines. The miR-155, miR-10a, miR-30a, miR-24-2* and miR-30c-2* were upregulated in sensitive cell lines, while expression of miR-200c, miR-203, miR-885-5p, miR-195 and miR-25* was increased in resistant cell line. Genes with significantly altered expression and putatively mediated by the expression-changed miRs were mainly enriched in chromatin assembly (MAF, HLF, BCL2, and IGSF3), anti-apoptosis (BCL2, IGF1 and IKBKB), protein kinase (NRP2, PAK7 and CDK5R1) (all the above genes were upregulated in sensitive cells) and small GTPase mediated signal transduction (GNA13, RAP2A, ARHGAP5 and RAB23, down-regulated in sensitive cells). Our results might provide potential biomarkers for gemcitabine sensitivity prediction and putative targets to overcome gemcitabine resistance in NSCLC patients.
吉西他滨是治疗晚期非小细胞肺癌（NSCLC）最常用的药物之一，但患者对吉西他滨的客观缓解率一般，因此有必要确定能从基于吉西他滨的治疗中获益的患者的新型生物标志物，并提高临床治疗效果。在这项研究中，应用对吉西他滨表现出不同敏感性的3种NSCLC细胞系进行mRNA和微小RNA（miR）表达芯片分析，以找出吉西他滨敏感性的生物标志物。在敏感细胞系中表达显著增加的基因主要富集在细胞黏附（NRP2、CXCR3、CDK5R1、IL32和CDH2）和分泌颗粒（SLC11A1、GP5、CD36和IGF1）中，而在耐药细胞系中表达显著上调的基因主要聚集在甲基化修饰（HIST1H2BF、RAB23和TP53）和氧化还原酶（TP53I3、CYP27B1和SOD3）中。最引人关注的是吉西他滨耐药的NSCLC细胞系中Wnt/β-连环蛋白信号通路的激活。miR-155、miR-10a、miR-30a、miR-24-2和miR-30c-2在敏感细胞系中上调，而miR-200c、miR-203、miR-885-5p、miR-195和miR-25*在耐药细胞系中表达增加。表达显著改变且可能由表达改变的miR介导的基因主要富集在染色质组装（MAF、HLF、BCL2和IGSF3）、抗凋亡（BCL2、IGF1和IKBKB）、蛋白激酶（NRP2、PAK7和CDK5R1）（上述所有基因在敏感细胞中上调）和小GTPase介导的信号转导（GNA13、RAP2A、ARHGAP5和RAB23，在敏感细胞中下调）中。我们的结果可能为吉西他滨敏感性预测提供潜在的生物标志物，并为克服NSCLC患者的吉西他滨耐药性提供假定的靶点。
