Dataset Information

DOCK8 Serves as a Prognostic Biomarker and Is Related to Immune Infiltration in Patients With HPV Positive Head and Neck Squamous Cell Carcinoma.

ABSTRACT:

Purpose

Dedicator of cytokinesis 8 (DOCK8) was reported to have a vital link to immunoregulation. However, the mechanisms by which it drives immune infiltration in cancer remain uncertain. We tried to assess the role of DOCK8 in patients with cancer, especially human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC).

Methods

Data on the expression and survival of DOCK8 in patients with various cancers were analyzed using the Oncomine and TIMER databases. The TIMER database assessed the relationship of DOCK8 with immune infiltration levels and various markers of multiple immune cells. Gene set enrichment analysis revealed tumor-associated biological processes related to DOCK8. ENCODE database was used to explore relevant transcription factors of DOCK8, and a PPI network was constructed using GENEMINIA. The expression and survival role of DOCK8 was confirmed in patients from independent GEO datasets.

Results

We determined that DOCK8 expression was upregulated or downregulated in various cancers unlike in healthy tissues. A high expression of DOCK8 was significantly correlated with a favorable prognosis in HPV-positive HNSCC and lung adenocarcinoma (LUAD). Furthermore, multivariate Cox regression analysis revealed that DOCK8 was an independent prognostic factor of HPV-positive HNSCC. Additionally, elevated DOCK8 expression was positively correlated with multiple immune cell infiltration levels and immune marker expression associated with particular immune cell subsets. Also, 14 pathways involved in immune activities and carcinogenesis, 22 potential TFs, and co-expression proteins of DOCK8 indicated DOCK8 to be related to tumor-associated biological processes. Ultimately, we verified that DOCK8 is upregulated and confers a favorable overall survival and progression-free survival status in patients with HPV-positive HNSCC.

Conclusion

These results elucidate that high expression of DOCK8 indicates a favorable prognosis in patients with HPV-positive HNSCC as well as increased microenvironmental immune infiltration levels. It would provide new insights into the prognosis predicting and clinical regimen decision making in patients with HPV-positive HNSCC.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC8482706 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Head and neck squamous cell carcinoma (HNSC) is an aggressive type of cancer that lacks early detection, and therefore, has a low 5-year survival rate. The spermine synthase (SMS) gene has been shown to be associated with Snyder-Robinson syndrome and poor prognosis of multiple cancers; however, its regulatory role in HNSC has never been investigated. Therefore, we explored the potential predictive value of SMS in HNSC. We explored the association between SMS expression and clinicopathological parameters of HNSC patients by using data from The Cancer Genome Atlas datasets (TCGA). The prognostic value of SMS was evaluated using the Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis (GEPIA) 2 and univariate and multivariate Cox regression analyses. We further used gene set enrichment analysis (GESA) to investigate the potential roles of SMS in HNSC prognosis and Tumor Immunity Estimation Resource 2.0 (TIMER2.0) to analyze the correlation between immune cell infiltration and SMS expression. Finally, starBase was used to screen out prognosis-associated non-coding RNA genes to constructed the competing endogenous RNA (ceRNA) network. Co-expression and survival analyses were used to identify the ceRNA network's effect on HNSC prognosis. We found that SMS expression was increased in HNSC compared with normal tissues (P<0.05). In addition, SMS expression was associated with tumor grade (P=0.006), N stage (P=0.001), and prognosis. Survival analysis revealed that high expression of SMS showed worse overall survival (OS) (HR =1.4, P=0.01) and worse disease-free survival (DFS) (HR =1.5, P=0.014). Multivariate Cox analysis further supported the prognostic value of SMS in HNSC (HR =1.006636, P=0.0056). GESA showed that SMS was involved in metabolism- and immune-related pathways. The immune infiltration analyses results showed a decrease in the landscape of immune cell infiltration with high SMS expression and SMS deletion in HNSC. Finally, a ceRNA network (SMS/hsa-miR-23b-3p/KTN1-AS1 and VPS9D1-AS axis) was constructed based on the co-expression and survival analyses in HNSC. Our findings first revealed that SMS functioned as a potential prognostic biomarker and provide insights into the molecular mechanisms of its function in HNSC. The use of SMS may be powerful for determining worse prognosis HNSC patients.

Project description:ObjectiveWe investigated the correlations between cyclin-dependent kinase 4/6 (CDK4/6) levels and human papillomavirus (HPV) infection state in head and neck squamous cell cancer (HNSCC). The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC.MethodsMultiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas (TCGA), and the mRNA levels and copy number variations (CNVs) of CDK4 and CDK6 were strictly analyzed. Overall survival (OS) curves were produced using the Kaplan-Meier method, and survival differences between groups were assessed by the log-rank test. Next, gene set enrichment analysis (GSEA) was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC. Last, lymphoid cell infiltrates in each type of HNSCC were explored, and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource (TIMER) analysis.ResultsOverexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV- HNSCC (CDK6: top 40%vs. bottom 40%, P=0.885; CDK4: top 40% vs. bottom 40%, P=0.267). In HPV+ HNSCC, CDK6 but not CDK4 was a relevant factor for OS (CDK6: top 40% vs. bottom 40%, P=0.002; CDK4: top 40% vs. bottom 40%, P=0.452). GSEA found that overexpressed CDK6 in HPV+ HNSCC inhibited pathways involved in the tumor immune response, suggesting its roles in antitumor immunity. TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+ HNSCC, which led to tumor response suppression.ConclusionsCDK6, but not CDK4, is a poor prognostic marker specific in HPV+ HNSCC patients. Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity. Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.