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

Objectives: Iodine-125 (I-125) irradiation has been widely applied in the treatment of advanced multiple malignant tumors. However, the underlying mechanism of I-125 exerted an anti-tumor effect on hepatocellular carcinoma (HCC) was largely unknown. Methods: In both HCCLM3 and SMMC-7721 cells, the effect of I-125 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 I-125 seed implantation on the tumor growth and Warburg effect in vivo. Results: I-125 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 I-125 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, I-125 irradiation significantly decreased the Warburg effect and exhibited anti-tumorigenesis function through upregulating the inhibitory effect of miR-338 on PFKL expression. Conclusion: I-125 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.