Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
BMC Cancer. 2019 Jan 14;19(1):64. doi: 10.1186/s12885-018-5243-3.
Radiotherapy is an indispensable treatment modality in head and neck cancer (HNC), while radioresistance is the major cause of treatment failure. The aim of this study is to identify a prognostic molecular signature associated with radio-resistance in HNC for further clinical applications.
Affymetrix cDNA microarrays were used to globally survey different transcriptomes between HNC cell lines and isogenic radioresistant sublines. The KEGG and Partek bioinformatic analytical methods were used to assess functional pathways associated with radioresistance. The SurvExpress web tool was applied to study the clinical association between gene expression profiles and patient survival using The Cancer Genome Atlas (TCGA)-head and neck squamous cell carcinoma (HNSCC) dataset (n = 283). The Kaplan-Meier survival analyses were further validated after retrieving clinical data from the TCGA-HNSCC dataset (n = 502) via the Genomic Data Commons (GDC)-Data-Portal of National Cancer Institute. A panel maker molecule was generated to assess the efficacy of prognostic prediction for radiotherapy in HNC patients.
In total, the expression of 255 molecules was found to be significantly altered in the radioresistant cell sublines, with 155 molecules up-regulated 100 down-regulated. Four core functional pathways were identified to enrich the up-regulated genes and were significantly associated with a worse prognosis in HNC patients, as the modulation of cellular focal adhesion, the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the regulation of stem cell pluripotency. Total of 16 up-regulated genes in the 4 core pathways were defined, and 11 over-expressed molecules showed correlated with poor survival (TCGA-HNSCC dataset, n = 283). Among these, 4 molecules were independently validated as key molecules associated with poor survival in HNC patients receiving radiotherapy (TCGA-HNSCC dataset, n = 502), as IGF1R (p = 0.0454, HR = 1.43), LAMC2 (p = 0.0235, HR = 1.50), ITGB1 (p = 0.0336, HR = 1.46), and IL-6 (p = 0.0033, HR = 1.68). Furthermore, the combined use of these 4 markers product an excellent result to predict worse radiotherapeutic outcome in HNC (p < 0.0001, HR = 2.44).
Four core functional pathways and 4 key molecular markers significantly contributed to radioresistance in HNC. These molecular signatures may be used as a predictive biomarker panel, which can be further applied in personalized radiotherapy or as radio-sensitizing targets to treat refractory HNC.
放射治疗是头颈部癌症（HNC）不可或缺的治疗方式，而放射抵抗是治疗失败的主要原因。本研究旨在确定与 HNC 放射抵抗相关的预后分子特征，以便进一步临床应用。
使用 Affymetrix cDNA 微阵列对 HNC 细胞系和同源放射抗性亚系之间的不同转录组进行全局调查。使用 KEGG 和 Partek 生物信息学分析方法评估与放射抵抗相关的功能途径。使用 SurvExpress 网络工具研究 TCGA-头颈部鳞状细胞癌（HNSCC）数据集（n=283）中基因表达谱与患者生存之间的临床关联。使用国家癌症研究所的基因组数据共享（GDC）-数据门户从 TCGA-HNSCC 数据集（n=502）中检索临床数据后，进一步通过 Kaplan-Meier 生存分析进行验证。生成一个面板制作分子来评估该分子对头颈部癌症患者放射治疗预后预测的疗效。
在放射抗性细胞亚系中发现 255 种分子的表达显著改变，其中 155 种上调，100 种下调。确定了 4 个核心功能途径来富集上调基因，并与 HNC 患者的预后不良显著相关，包括细胞焦点粘附的调节、PI3K-Akt 信号通路、HIF-1 信号通路和干细胞多能性的调节。在这 4 个核心途径中定义了 16 个上调基因，其中 11 个过度表达的分子与 HNC 患者接受放疗后的不良生存相关（TCGA-HNSCC 数据集，n=283）。其中，4 种分子被独立验证为与接受放疗的 HNC 患者不良生存相关的关键分子（TCGA-HNSCC 数据集，n=502），包括 IGF1R（p=0.0454，HR=1.43）、LAMC2（p=0.0235，HR=1.50）、ITGB1（p=0.0336，HR=1.46）和 IL-6（p=0.0033，HR=1.68）。此外，这 4 种标志物的联合使用可以很好地预测 HNC 的放射治疗效果不佳（p<0.0001，HR=2.44）。
4 个核心功能途径和 4 个关键分子标志物显著促进了 HNC 的放射抵抗。这些分子特征可作为预测生物标志物组，可进一步应用于个性化放疗或作为放射增敏靶点治疗难治性 HNC。
