Abstract: Objective:To investigate the expression and clinicopathological significance of miR-138 and FOXD1 in oral squamous cell carcinoma (OSCC). Methods:Forty-four patients with primary OSCC who underwent radical operation were included. The expression of miR-138 and FOXD1 in tumor tissues and paired normal tissues was detected by real-time fluorescent quantitative polymerase chain reaction (qRT-PCR). Chi-square test and Kaplan-Meier survival analysis were used to analyze the relationship between miR-138 expression and clinicopathological features. The gain-of-function experiments in vitro were performed to elucidate the role of miR-138 in OSCC cell line Cal27 by grouping into miR-NC group and miR-138 mimics group. CCK-8 proliferation test was used to detect cell proliferation, Transwell invasion test was used to detect cell invasion, and the role of miR-138 on the biological behavior of OSCC cells were observed. In addition, bioinformatics predictions were used to investigate the potential target genes of miR-138. The effect of miR-138 on FOXD1 expression was determined by Western blot. After co-transfection of miR-138 mimics and sh-FOXD1, the effects of sh-FOXD1 on the biological behavior of OSCC were detected, and the targeting effect of miR-138 on FOXD1 was verified by dual-luciferase reporter assay. Results:The miR-138 expression was significantly down-regulated in OSCC tissues and cell lines (P<0.05). The miR-138 expression was positive related to primary tumor size, lymph node metastasis, TNM stage and prognosis (P<0.05). Up-regulation of miR-138 expression can significantly inhibit the proliferation and invasion of Cal27 cells, and can reduce the expression of FOXD1 in Cal27 cells (P<0.01). FOXD1 overexpression could partially reverse the proliferation and invasion activity of OSCC cells inhibited by transfecting miR-138 mimics. The dual-luciferase reporter assay showed that overexpression of miR-138 significantly inhibited the luciferase activity in FOXD1-wild type group (P<0.05). However, miR-138 mimics did not change the luciferase activity in FOXD1-mutant group. Conclusions:miR-138 inhibits the proliferation and invasion of OSCC by regulating FOXD1 expression. miR-138-FOXD1 axis may be a potential therapeutic target against OSCC.