CD44 occurring alternative splicing promotes cisplatin resistance and evokes tumor immune response in oral squamous cell carcinoma cells.

Background: Oral squamous cell carcinoma (OSCC) is the most prevalent malignant tumor in head and neck region. Platinum drug resistance limits the clinical application of chemotherapy regardless of medical development. The aim of our study is to identify cisplatin-resistant genes which can be used as new therapeutic targets and investigate the functional mechanism of OSCC chemoresistance.

Methods: The OSCC Cal27 and HSC4 cisplatin-resistant cell lines were constructed to screen the differential genes/transcripts expression. GO, KEGG and GSEA were performed to reveal the relevant signaling pathways. Alternative splicing (AS) software rMATs was applied to explore AS events in chemoresistance. R package and TIMER tools were used to evaluate the linear correlation between CD44 and immune cell subpopulations. The co-culture model of dendritic cells (DCs) and OSCC cells was applied to explore the effect of CD44 on immune microenvironment and cisplatin resistance.

Results: Our results showed that CD44 was differentially expressed in cisplatin-resistant OSCC cells. Through bioinformatics prediction and experimental verification, we confirmed that CD44 occurring AS was involved in tumor progression and cisplatin resistance. Moreover, CD44 could further enhance the cisplatin resistance of OSCC by activating DCs, making CD44 to be a potential intervention target. We also identified DC as a new target for platinum drugs to stimulate the growth of OSCC.

Conclusion: Our findings not only make it possible to explore new therapeutic methods, such as CD44 inhibitors or antisense oligonucleotides, but also provide insights into the new mechanisms of cisplatin resistance to chemotherapy.