人乳头状瘤病毒阳性的头颈鳞状细胞癌特异性基因生物信息学研究

目的分析人乳头状瘤病毒(HPV)阳性的头颈鳞状细胞癌(鳞癌)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，从中筛出差异基因进行基因本体分析及京都基因和基因组(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信息门户以及癌症基因组图谱(TCGA)数据库验证这些特异基因在HPV(+)与HPV(-)头颈鳞癌中的表达差异并分析特异基因与头颈鳞癌患者生存预后的相关性。结果从数据集GSE52088与GSE39366中筛选出42个共同差异基因，其中上调基因25个，下调基因17个，经Cytoscape两轮筛选确定白介素-6(IL-6)、细胞表面标记物CD44、基质金属蛋白酶1(MMP1)、CXC趋化因子配体基序1(CXCL1) 4个特异基因。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、肿瘤坏死因子(TNF)信号通路途径等信号通路(P < 0.01)。经TCGA数据库以及Cbioportal检验证实特异基因在HPV(+)与HPV(-)头颈鳞癌中的表达差异，且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，IL-6、CD44与头颈鳞癌预后存在相关性，有望成为治疗HPV(+)头颈鳞癌的潜在靶点。

Bioinformatics analysis of specific genes in the HPV-positive head and neck squamous cell carcinoma

ObjectiveTo analyze the specific genes and key signaling pathways of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), thus further to screen valuable biomarker for diagnosis and target treatment for HPV-positive HNSCC, which will provide reference for further study of tumor mechanism.MethodsGene chips from HNSCC patients with the information of HPV infection 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 discrepant expression level of these specific genes in HPV(+) and HPV(-) head and neck squamous carcinoma were validated and the relationship between the specific genes expression and the prognosis of HNSCC patients were explored through searching database.ResultsA total of 556(305 and 251)differential genes were screened out from GSE52088 and GSE39366 respectively. Among 42 common differential genes, 25 genes were up-regulated and 17 genes down-regulated. Four specific genes including IL-6 (interleukin 6), CD44, MMP-1 (matrix metallopeptidase 1) and CXCL1 (CXC motif chemokine ligand 1) were identified by Cytoscape in two rounds. 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 discrepancy of specific genes in HPV(+) versus HPV(-) head and neck squamous carcinomas has been validated. 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.Conclusions Different specific genes were found in HPV-positive HNSCC tissues, which were probably involved in different signal pathways regulation and tumorigenesis. IL-6, CD44, MMP1, CXCL1 were the specific genes. MMP1 and CXCL1 were potential biomarkers for diagnosis and prognosis prediction of HPV(+)HNSCC.IL-6, CD44 were correlated with the prognosis of HNSCC, which were expected to be potential targets for HPV(+) HNSCC treatment.