Understanding the role of potential pathways and its components including hypoxia and immune system in case of oral cancer

Abstract

There are a few biological functions or phenomenon which are universally associated with majority of the cancers and hypoxia and immune systems are among them. Hypoxia often occurs in most of the cancers which helps the cells in adapting different responses with respect to the normal cells which may be the activation of signaling pathways which regulate proliferation, angiogenesis, and cell death. Similar to it, immune signaling pathways are known to play critical roles in cancers. Moreover, there are a number of genes which are known to be associated with these hypoxia and immune system and appear to direct affect the tumor growth and propagations. Cancer is among the leading cause of death and oral cancer is the tenth-leading cause due to cancer death. In this study, we were mainly interested to understand the impact of alteration in the expression of hypoxia and immune system-related genes and their contribution to head and neck squamous cell carcinoma. Moreover, we have collected the genes associated with hypoxia and immune system from the literatures. In this work, we have performed meta-analysis of the gene and microRNA expression and mutational datasets obtained from public database for different grades of tumor in case of oral cancer. Based on our results, we conclude that the critical pathways which dominantly enriched are associated with metabolism, cell cycle, immune system and based on the survival analysis of the hypoxic genes, we observe that the potential genes associated with head and neck squamous cell carcinoma and its progression are STC2, PGK1, P4HA1, HK1, SPIB, ANXA5, SERPINE1, HGF, PFKM, TGFB1, L1CAM, ELK4, EHF, and CDK2.

Figure 1

Differential gene expression profiling of different grades of oral cancer. (a) Venn diagram for differentially expressed genes, inferred, and enriched pathways; (b) Plot to show the overall number of DEGs, inferred, and enriched pathways.

Figure 2

Differentially expressed genes and the enriched pathways for HPV infected oral cancer. Venn diagram for the different combinations of DEGs and the enriched pathways for (a,b) GSE31056 and (c) NGS dataset. (d) Heatmap and cluster for the 152 commonly DEGs in case of NGS data. (e) Commonly enriched 32 pathways for NGS dataset and the p-values for these pathways including the array dataset.

Figure 3

Mutational profiling and functional impact in oral cancer. (a) We have performed pathway enrichment analysis for those genes which appear to have more than 5% mutation for the selected dataset from TCGA database; (b) Genes with mutations ≥ 10%; (c) Comparison of the altered functions with respect to mutations and differential expression; (d) p-value for Kaplan-Meyer plots after survival analysis of the hypoxic genes in case of head and neck cancer.

Figure 4

Clinical relevance. Clinical Relevance for the top-ranked genes (based on connectivity of the genes within the network generated through network database) and respective inferred pathways. p-value represents the clinical significance in terms of survival analysis and the TCGA database and cBioPortal have been used.

Figure 5

miRNA expression profiling and their functional impact in head and neck cancer. (a) Differentially expressed miRNAs and (b) the enriched pathways with the respective miRNAs.