Abstract: Objective To explore the effect of microRNA-6852 (miR-6852) on the radiosensitivity of colon cancer cells SW480 and its possible mechanism. Methods Human normal colonic epithelial cells HCoEpiC and human colon cancer cells SW480 were cultured in vitro, and the cells were irradiated with X-ray radiation field. The cells were transfected with miRNA negative control (miR-NC), overexpression vector negative control (oe-NC), shRNA negative control (sh-NC), mir-6852-mimic, LEF1 overexpression vector (oe-LEF1) and AKR1C3-specific shRNA (sh-AKR1C3). Then, qRT-PCR and Western blot were used to detect the expression of miR-6852, lymphoid enhancer-binding factor 1 (LEF1) and aldo-keto reductase family 1 member C3 (AKR1C3) in cells. The dual luciferase reporter gene experiment was used to detect the targeted binding of miR-6852 to LEF1, LEF1 and AKR1C3. The EdU assay was used to detect cell proliferation. Flow cytometry was used to detect cell apoptosis. ChIP-PCR was used to detect the targeted binding of LEF1 to the AKR1C3 promoter region. Results Compared with the HCoEpiC group, the SW480 group presented significant decreases in the expression of miR-6852 (P＜0.05), and increases in the expression of LEF1 mRNA and protein, and the expression of AKR1C3 mRNA and protein were significantly increased (P＜0.05). Compared with the blank control group, SW480 cells in the 2Gy group, 4Gy group and 6Gy group showed remarkably reduced expression of miR-6852 (P＜0.05), and increases in the expression of LEF1 mRNA and protein, and the expression of AKR1C3 mRNA and protein (P＜0.05). Compared with the miR-NC+oe-NC+6Gy group, the miR-6852-mimic+oe-NC+6Gy group showed significantly decreases in the number of EdU positive cells in SW480 cells (P<0.05), while the apoptosis rate was significantly increased (P<0.05). Compared with the miR-6852-mimic+oe-NC+6Gy group, the number of EdU-positive cells in the miR-6852-mimic+oe-LEF1+6Gy group was significantly increased (P<0.05), while the apoptosis rate was significantly reduced (P<0.05). Compared with the oe-NC+sh-NC+6Gy group, the number of EdU-positive cells in the oe-LEF1+sh-NC+6Gy group was significantly increased (P＜0.05), and the apoptosis rate was significantly reduced (P＜0.05) . Compared with the oe-LEF1+sh-NC+6Gy group, the number of EdU-positive cells in the oe-LEF1+sh-AKR1C3+6Gy group was significantly reduced (P<0.05), and the apoptosis rate was significantly increased (P<0.05). Conclusions MiR-6852 targets the LEF1/AKR1C3 axis to increase the sensitivity of colon cancer cells SW480 towards radiotherapy.