YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
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DOI：
10.1016/j.oraloncology.2014.06.003
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Roberg, Karin
中科院分区：
文献类型：
--
作者：
Jerhammar, Fredrik;Johansson, Ann-Charlotte;Roberg, Karin
目的：针对表皮生长因子受体（EGFR）的靶向治疗仅代表头颈鳞状细胞癌（HNSCC）的治疗进展。本研究解决了对 EGFR 靶向抗体西妥昔单抗 (Erbitux (R)) 治疗反应的生物标志物的需求。材料和方法：通过结晶紫测定评估 HNSCC 细胞系的内在西妥昔单抗敏感性。使用 Affymetrix SNP 6.0 平台对五种耐药细胞系和五种敏感细胞系进行基因拷贝数分析。使用定量实时 PCR 来验证选定的拷贝数变化并评估 mRNA 表达。采用 siRNA 技术研究了基因和 mRNA 水平上的发现的功能重要性。使用Mann-Whitney U 检验和Spearman 相关检验对数据进行统计评估。 结果：对32 个HNSCC 细胞系的内在西妥昔单抗敏感性的分析分别将5 个和9 个细胞系描述为西妥昔单抗敏感或耐药。对五种耐药细胞系和五种敏感细胞系进行基因拷贝数分析，鉴定出基因组区域 11q22.1 或 5p13-15 中的 39 个扩增的蛋白质编码基因，包括 YAP1。使用 qPCR 进行的评估证实 YAP1 扩增与西妥昔单抗耐药性相关。 YAP1 的扩增与较高的 mRNA 水平相关，而 RNA 敲低则导致西妥昔单抗敏感性增加。对公共领域的几个独立临床数据集的评估证实了 YAP1 在包括 HNSCC 在内的多种肿瘤类型中扩增，并且在 HNSCC 患者子集中存在高度差异表达。结论：综上所述，我们提供的证据表明 YAP1 可以代表 HNSCC 细胞系中西妥昔单抗耐药性的新型生物标志物基因。 (C) 2014 Elsevier Ltd. 保留所有权利。
Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)).Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearman's correlation test.Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients.Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines. (C) 2014 Elsevier Ltd. All rights reserved.