Tian Guocai, Fu You, Zhang Dahe, Li Jiang, Zhang Zhiyuan, Yang Xi
Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China.
Cancer Cell Int. 2021 Mar 12;21(1):167. doi: 10.1186/s12935-021-01863-6.
Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed.
Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein-protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed.
In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three-NVP-AUY922, fostamatinib and PP-2-greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo.
In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.
头颈部鳞状细胞癌（HNSCC）是一种全球常见的肿瘤，预后较差。人乳头瘤病毒（HPV）阳性和阴性的HNSCC发病机制不同。然而，在确定HNSCC生物标志物时，很少有研究考虑HPV状态。因此，迫切需要确定HPV阳性和阴性HNSCC的生物标志物。
分析来自基因表达综合数据库（GEO）的三个微阵列数据集，获得差异表达基因（DEG）。然后，进行功能富集通路分析并构建蛋白质-蛋白质相互作用（PPI）网络。在Oncomine、癌症基因组图谱（TCGA）和人类蛋白质图谱（HPA）中确定中心基因在mRNA和蛋白质水平的表达。此外，基于TCGA数据对患者按HPV状态和关键基因表达水平进行生存分析。通过基因集富集分析（GSEA）分析AREG、STAG3、CAV1和C19orf57在癌症中的作用。确定了十种小分子药物，并在六种HPV阴性HNSCC细胞系中进一步评估了唑尼沙胺、NVP-AUY922、PP-2和福斯替尼的治疗价值。最后，基于三种HPV阴性HNSCC模型在体内测试NVP-AUY922的治疗价值，并进行统计分析。
总共获得47个DEG，其中11个被确定为中心基因。生物学过程分析表明，中心基因与有丝分裂细胞周期的G1/S转换相关。生存分析发现，AREG、STAG3、C19orf57和CAV1在HPV阳性和阴性患者中的预后价值不同。基因集富集分析（GSEA）显示AREG、STAG3和CAV1在肿瘤失调通路中的作用。十种小分子被确定为专门针对HPV阳性或阴性患者的潜在药物；三种——NVP-AUY922、福斯替尼和PP-2——在体外显著抑制六种HPV阴性HNSCC细胞系的增殖，NVP-AUY922在体内抑制三种HPV阴性HNSCC异种移植瘤。
总之，AREG、STAG3、C19orf57和CAV1是HPV阴性HNSCC的关键预后因素和潜在治疗靶点。NVP-AUY922、福斯替尼和PP-2可能是治疗HPV阴性HNSCC的有效药物。
