125I suppressed the Warburg effect viaregulating miR-338/PFKL axis in hepatocellular carcinoma

Iodine-125 (125I) irradiation has been widely applied in the treatment of advanced multiple malignant tumors. However, the underlying mechanism of 125I exerted an anti-tumor effect on hepatocellular carcinoma (HCC) was largely unknown. In both HCCLM3 and SMMC-7721 cells, the effect of 125I irradiation on the glycolysis was detected. The mRNA in HCC tissues and cell lines were detected by RT-qPCR. Cell proliferation, invasion and migration, and apoptosis were examined by CCK-8, Transwell, wound healing assay and flow cytometry assay, respectively. The interaction between miR-338 and PFKL (6-phosphofructokinase) were verified by dual-luciferase reporter gene assay. Western blotting was used to detect the expression of glycolysis-related proteins. We also evaluated the effect of 125I seed implantation on the tumor growth and Warburg effect in vivo. 125I irradiation significantly decreased the Warburg effect, cell proliferation, invasion and migration, and induced apoptosis of HCCLM3 and SMMC-7721 cells. miR-338 was upregulated in HCC cells treated with 125I irradiation, which was a negative correlation with tumor size, tumor metastasis, and tumor development. Moreover, miR-338 directly interacted with PFKL and suppressed its expression. Mechanistically, 125I irradiation significantly decreased the Warburg effect and exhibited anti-tumorigenesis function through upregulating the inhibitory effect of miR-338 on PFKL expression. 125I irradiation upregulated the suppression of miR-338 on PFKL to downregulate the Warburg effect and anti-tumorigenesis in HCC and provided a new potential strategy for HCC clinical treatment.