A systems biology approach to uncover key genes and pathways mediating progression of leukoplakia to primary oral squamous cell carcinoma

Objective: Oral squamous cell carcinoma (OSCC) counts for 90% of pathology in oral cavity cancer. Oral leukoplakia is the most frequent type of pre-invasive lesion leading to OSCC. An integrated bioinformatics analysis was performed to determine key genes and pathways deregulated in the malignant transformation of leukoplakia to primary OSCC. Methods: Differentially expressed genes (DEGs) were determined in early OSCC compared to oral leukoplakia. A protein-protein interaction (PPI) network was constructed, clusters and hubs in the PPI network were identified, and prognostic hub genes in head and neck squamous cell carcinoma and OSCC were determined. The validation study was conducted for three of the markers at the protein level using the immunohistochemistry (IHC) assay. Results: A total of 901 DEGs in primary OSCC compared to leukoplakia were identified. Also, 113 hub genes were determined in the PPI network. Twenty-two hubs were linked with the prognosis of HNSCC patients. The combination of seven genes including PLAU, FADD, SERPINE1, FOSL1, PLAUR, FST, and THBS1 illustrated the most considerable prognostic impact in HNSCC. IRF1 and MAP2K6 were the main TF and protein kinase involved in the malignant transformation of oral leukoplakia to primary OSCC. The most significant pathways and biological processes deregulated in primary OSCC were associated with the immune system. IHC study confirmed the upregulation of PLAU, SERPINE1, and SPP1 in primary OSCC. Conclusions: The present results unraveled more details underlying the mechanisms involved in the malignant transformation of oral leukoplakia and may help the prognosis of patients with primary OSCC.