BACKGROUND

Oral squamous cell carcinoma (OSCC) has a poor postoperative recovery and is prone to drug resistance during long-term chemotherapy, but the molecular mechanism of its resistance has not been fully elucidated.

METHODS

In the present study, a cisplatin-resistant cell line Cal27R was established and the key genes and pathways associated with drug resistance were explored using bioinformatics analysis and molecular biology experimental techniques.

RESULTS

Transcriptome analysis reveals a total of 1927 differentially expressed genes (DEGs). GO and further KEGG analysis revealed the DEGs were primarily concentrated in the tumor necrosis factor (TNF) and the mitogen-activated protein kinase (MAPK) signaling pathway. PPI network analysis identified six genes exhibiting significant interactions. Among these, interrogation of the TCGA database revealed elevated expression levels of TNF, TGFB1, and IL1B in tumors from drug-resistant patients, whereas EGF and FOS expression was significantly downregulated. The level of immune infiltration was positive correlated with the expression of TNF, TGFB1, IL6 and EGF, conversely, negative correlated with that of IL1B. Furthermore, low expression of TNF and FOS, as well as high expression of TGFB1, IL6 and EGF, was associated with poor overall prognosis. Based on the comprehensive analysis above, TNF, TGFB1, and EGF were ultimately selected as target genes to positively regulate the cisplatin resistance of Cal27R cells. Furthermore, we validated the expression of target genes in human tongue carcinoma tissues and paired adjacent normal tissues. Knockout of these genes significantly reduced drug resistance, consistent with our initial hypothesis. Whole-exome sequencing (WES) analysis confirmed the absence of underlying mutations, thereby corroborating the bioinformatics predictions.

CONCLUSION

TNF, TGFB1 and EGF were regarded as the key genes associated with cisplatin resistance and poor prognosis in OSCC. Meanwhile, their related TNF and MAPK pathways were considered as the pivotal signaling pathways. Our results provide a theoretical and experimental basis for potential diagnostic and therapeutic targets to address drug resistance in clinical settings.