Genomic insights into oral cancer highlight mutant SIGMAR1 as a critical target to overcome chemoresistance
Oral cancer (OC) is a highly aggressive malignancy characterized by uncontrolled cell proliferation in the oral cavity. Recent studies have highlighted the role of Sigma-1 receptor (SIGMAR1) mutations in cancer progression, disrupting cellular homeostasis, altering gene and protein expression, and promoting drug resistance. However, its role in OC remains scarce. This study investigated SIGMAR1 mutations, expression profiles, and their potential link to drug resistance in OC. Using 2,008 OC samples from the TCGA Pan-Cancer Atlas, we identified SIGMAR1 genetic alterations in 4% of cases, including missense mutations, deletions, and amplifications. In the HN13 OC cell line, Sanger sequencing revealed a novel heterozygous Asp-to-Gly (c.585C>G) missense mutation. Quantitative RT-PCR and Western blot analyses showed SIGMAR1 overexpression in HN13 cells compared to non-tumor oral keratinocytes (NOK-SI). Silencing SIGMAR1 increased HN13 cell sensitivity to cisplatin, indicating its role in drug resistance. This study is the first to report the c.585C>G mutation in SIGMAR1 and demonstrate its contribution to cisplatin resistance, a major chemotherapy challenge to OC treatment. These findings highlight SIGMAR1's critical role in OC pathogenesis and its potential as a therapeutic target to overcome chemoresistance. The results also pave the way for future research into RNA-based therapies and precision oncology interventions.