Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism that is demonstrated to be involved in tumor progression through both energy supply of fatty acid (FA) oxidation and enhancing cancer cell malignance. The aim of this study was to investigate whether MAGL could be a potential therapeutic target and prognostic indicator for hepatocellular carcinoma (HCC). To evaluate the relationship between MAGL levels and clinical characteristics, a tissue microarray (TMA) of 353 human HCC samples was performed. MAGL levels in HCC samples were closely linked to the degree of malignancy and patient prognosis. RNA interference, specific pharmacological inhibitor JZL-184 and gene knock-in of MAGL were utilized to investigate the effects of MAGL on HCC cell proliferation, apoptosis, and invasion. MAGL played important roles in both proliferation and invasion of HCC cells through mechanisms that involved prostaglandin E2 (PGE2) and lysophosphatidic acid (LPA). JZL-184 administration significantly inhibited tumor growth in mice. Furthermore, we confirmed that promoter methylation of large tumor suppressor kinase 1 (LATS1) resulted in dysfunction of the Hippo signal pathway, which induced overexpression of MAGL in HCC. These results indicate that MAGL could be a potentially novel therapeutic target and prognostic indicator for HCC.
The combination of radiotherapy and immunotherapy has shown great promise in eradicating tumors. For example, 125I radioactive particle implantation and cytokine-induced killer cell therapies have demonstrated efficacy in treating hepatocellular carcinoma. However, the mechanism of this combination therapy remains unknown. In this study, we utilized cytokine-induced killer cells obtained from human peripheral blood mononuclear cells along with 125I radioactive particle implantation to treat subcutaneous hepatocellular carcinoma xenograft tumors in BALB/c nude mice. The effects of combination therapy on tumor growth, tumor cell apoptosis and proliferation, animal survival, and immune indexes were then assessed. The results indicated that 125I radioactive particle implantation combined with cytokine-induced killer cells shows a much greater antitumor therapeutic effect than either of the therapies alone when compared to control treatments. Mice treated with a combination of radiotherapy and immunotherapy displayed significantly reduced tumor growth. 125I radioactive particle implantation upregulated the expression of major histocompatibility complex (MHC) class I chain-related gene A in hepatocellular carcinoma cells and enhanced cytokine-induced killer cell–mediated apoptosis through activation of caspase-3. Furthermore, cytokine-induced killer cells supplied immune substrates to induce a strong immune response after 125I radioactive particle implantation therapy. In conclusion, 125I radioactive particle implantation combined with cytokine-induced killer cell therapy significantly inhibits the growth of human hepatocellular carcinoma cells in vivo and improves animal survival times through mutual promotion of antitumor immunity, presenting a promising therapy for hepatocellular carcinoma.
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