Identification of four key prognostic genes and three potential drugs in human papillomavirus negative head and neck squamous cell carcinoma

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma

“…However, STAG3 overexpression is also a common event in various cancers [186]. In HNSCCs not stratified by HPV status, STAG3 expression is associated with improved overall survival and progression-free interval [143]. Conversely, high STAG3 expression is associated with poor prognosis, metastasis, and disease recurrence in colorectal cancer patients [187].…”

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

“…In another recent study, fostamatinib (which inhibits PLK1 as well as other serine-threonine kinases) was shown to be effective against the prostate cancer cell line (PC3) [102]. The anti-cancer activity of fostamatinib was also evident against head and neck squamous cell carcinoma [103], hepatocellular carcinoma [104], breast cancer [105], and diffuse large B cell lymphoma [106] cell lines. Moreover, a fostamatinib derivative, NSC765691, also exhibited antiproliferative activity against the panel of NCI-60 cell lines [107].…”

Overview of Candida albicans and Human Papillomavirus (HPV) Infection Agents and their Biomolecular Mechanisms in Promoting Oral Cancer in Pediatric Patients

“…A gradual decrease in expression of TGF- β , TGF β R-I, and TGF β R-II was observed in the different stages of carcinogenesis. In cancer cells, there is a reduction in TGF β R-II levels, and this can promote the development and growth of oral cancer, acting as an indicator of differentiation and therefore of aggressive behavior [ 110 ]. Activation of the Wnt/ β -catenin pathway induces β -catenin release and subsequently cytoplasmic aggregation and its transport to the nucleus, through the interaction with certain genes (with inhibition of apoptosis and increase of cell proliferation) such as COX-2, cyclin D1, and cMyc [ 105 , 111 ].…”