〔Abstract〕 Objective To investigate the expression of sigma-1 receptor in oral squamous cell carcinoma(OSCC) tissues and cell lines, reduce the expression of sigma-1 receptor in OSCC cells by transfection with specific siRNA, detect the effect on their biological behavior, and preliminarily analyze the possible mechanism. Methods The expression of sigma-1 receptor in human OSCC tissues were detected by immunohistochemistry. Western blot and immunofluorescence were used to detect the expression of sigma-1 receptor in human OSCC cell lines. GEPIA database was used to analyze the correlation between sigma-1 receptor expression level and prognosis of patients withOSCC. The expression of sigma-1 receptor was down-regulated by transfection of specific siRNA. Then the proliferation, migration and invasion of OSCC cells after transfection were detected by CCK-8 and Transwell assay, and the expression level of voltage-gated sodium ion channels subtype Nav1.5 in OSCC cells was detected by qRT-PCR and Western blot. Results Immunohistochemical analysis showed that the expression of sigma-1 receptor was higher in OSCC tissues than that in normal tissues. Western blot revealed that the sigma-1 receptor was expressed in all four OSCC cell lines. The results of GEPIA database analysis showed that the expression level of sigma-1 receptor was negatively correlated with the overall survival rate of patients with OSCC. Immunocytochemistry and confocal microscopy showed that the sigma-1 receptor was mainly localized in the plasma membrane in CAL-27 cells. CCK-8 analysis showed that the down-regulated expression of sigma-1 receptor reduced the proliferation of CAL-27 cells through its specific siRNA. Transwell analysis showed that the reduced expression of sigma-1 receptor significantly inhibited the migration and invasion of CAL-27 cells. In addition, down-regulation of sigma-1 receptor expression was found to inhibit the protein and mRNA expression levels of Nav1.5. Conclusion sigma-1 receptor participates in the occurrence and development of OSCC, promotes the proliferation, migration and invasion of OSCC cells, and may be involved in the progression of OSCC by regulating the Nav1.5.