Comparative Transcriptomic Analysis of Oral Squamous Cell Carcinoma with Progressive Cisplatin Resistance

Therapy resistance remains a major cause of cancer-related mortality. Cisplatin (cis-diamminedichloroplatinum, CDDP) is a first-line chemotherapeutic agent for oral cancer, but intrinsic and acquired resistance substantially limit its clinical efficacy. Epithelial–mesenchymal transition (EMT) has been associated with drug resistance across multiple tumor types; however, its involvement in cisplatin resistance in oral cancer remains incompletely understood. Here, we established an in vitro model of cisplatin resistance using the squamous cell carcinoma 9 (SCC-9) cell line and generated two populations with distinct resistance levels. We observed morphological and transcriptional changes consistent with EMT-related features, including increased mRNA expression of Vimentin, SNAIL1, ZEB1, ZEB2, and CDH2. Resistant cells also exhibited reduced proliferation, whereas the intermediately resistant population, cisplatin-resistant 4 (CPR4), showed greater wound closure, suggesting enhanced migratory behavior and features consistent with a hybrid-like EMT state. Conversely, the more resistant subline, cisplatin-resistant 8 (CPR8), exhibited a more stationary phenotype. Transcriptomic profiling by RNA sequencing (RNA-seq) revealed extensive differential gene expression associated with EMT and cisplatin resistance. Functional enrichment analyses identified Gene Ontology (GO) terms related to cell adhesion, extracellular matrix organization, and calcium ion binding, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed enrichment of PI3K/Akt signaling. Together, our findings support a dynamic model in which distinct EMT-related transcriptional states are associated with different levels of cisplatin resistance. This study provides insights into transcriptional changes associated with resistance acquisition and highlights candidate genes and pathways for further investigation and functional validation in oral cancer.