HPV阳性头颈鳞癌的特异性基因生物信息学研究分析

Analysis of Specific Genes of the HPV-positive Head and Neck Squamous Cell Carcinoma by Bioinformatics

摘要:

目的 分析人乳头瘤病毒(human papilloma virus，HPV)阳性头颈鳞癌(head and neck squamous cell carcinoma，HNSCC)的特异表达基因及关键信号通路，为HPV相关头颈鳞癌筛选有价值的基因标记物，并为进一步的肿瘤机制研究提供参考。 方法 从GEO高通量基因芯片数据库中筛选出头颈鳞癌具有 HPV感染信息的芯片组织共136例，其中HPV(+)组织20例、HPV(-)组织116例。筛出差异表达基因(differentially expressed genes，DEG)，进行基因本体(Gene ontology，GO)分析及京都基因和基因组(Kyoto encyclopedia of genes and genomes,KEGG)信号通路富集分析，并筛出头颈鳞癌的特征基因簇和通路，以及关键基因并进行蛋白质相互作用网络可视化分析。通过Cbioportal 信息门户(cBio Cancer Genomics Portal)以及癌症基因组图谱(the cancer genome atlas，TCGA)数据库验证这些核心基因的表达水平与头颈鳞癌患者生存预后的相关性。 结果 从组织芯片检测的4877个基因中共筛选出556个差异表达基因，42个共同差异基因，其中上调基因25个，下调基因17个，经Cytoscape两轮筛选确定IL-6(interleukin 6)、CD44(CD44-molecule)、MMP-1(matrix metallopeptidase-1)、CXCL1(C-X-C motif chemokine ligand1)4个关键基因。信号通路富集分析显示共同差异基因参与细胞周期、NOD样受体信号通路、TNF信号通路途径等信号通路(P<0.01)。经TCGA数据库以及Cbioportal检验证实IL-6、CD44表达水平与头颈鳞癌生存预后呈负相关(P<0.01)。 结论 HPV(+)头颈鳞癌具有特异性基因表达，并可能参与关键信号通路调控肿瘤的发生发展。IL-6、CD44、MMP1、CXCL1 4个特异基因可能参与HPV(+)头颈鳞癌发展及侵袭过程，其中MMP1、CXCL1有望作为诊断及预后的标志物，IL6、CD44与头颈部鳞癌预后明显相关，有望成为治疗HPV(+)头颈鳞癌的潜在靶点。

Abstract:

Objective To explore differential genes (DEG) and key pathways between human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC)，thus further to screen valuable biomarker for diagnosis and target treatment for HPV-positive HNSCC. Methods A total of 136 gene chips from HNSCC patients with the information of HPV infection (20 cases of HPV-positive cancer tissue and 116 cases of HPV-negative cancer) were selected in GEO (Gene Expression Omnibus，GEO) database. Then，the screened DEG cluster were performed for Gene ontology (GO) analysis and signal pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed and specific genes were identified，and further protein interaction network visualization was analyzed. Finally，the relationship between the specific genes expression and the prognosis of HNSCC patients were explored through searching database. Results A total of 42 DEGs were screened out from more than 4877 genes detected in the chips，including 25 up-regulated genes and 17 down-regulated ones，IL6 (interleukin 6)，CD44 (CD44 molecule)，MMP1 (matrix metallopeptidase 1)，CXCL1 (CXC motif chemokine ligand 1) were identified after 2 rounds of screening. Signal pathway enrichment analysis showed that specific genes were involved in NOD-like receptor signaling pathway，TNF signaling pathway and other major signaling pathways (P<0.01). The expression of IL-6 and MMP1 were negatively correlated with the survival prognosis of HNSCC (P<0.01)，which was confirmed by the TCGA database and Cbioportal test. Conclusion Different specific genes were found in HPV-positive and -negative HNSCC tissues，which were probably involved in different signal pathways regulation and tumorigenesis. IL-6，CD44，MMP1，CXCL1 were the specific genes，MMP1，CXCL1 were potential biomarkers for diagnosis and prognosis prediction of HPV(+)HNSCC，IL6，CD44 were expected to be potential targets for HPV(+) HNSCC treatment.