Abstract
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.
Highlights
Liver cells obtain energy through fatty acid (FA) β-oxidation
Since Nomura et al first reported the tumor promoting effects of MAGL7, increasing studies investigating the relationship between Monoacylglycerol lipase (MAGL), carcinogenesis, and tumor progression have been performed to reveal insights into the relevant mechanisms
The role of MAGL in tumorigenesis and progression remains controversial due to the fact that tumor suppressing effects of MAGL are observed in some colorectal cancers[8,19]
Summary
Liver cells obtain energy through fatty acid (FA) β-oxidation. according to Warburg’s theory, tumor cells favor glycolysis for energy production[5]. MAGL is a key enzyme in lipid metabolism and participates in the last step of neutral lipid decomposition which resolves monoacylglycerol into fatty acid and glycerol. The MAGL-free fatty acid (FFA) pathway has recently emerged as a critical pathway that promotes tumor growth and invasion[7]. MAGL is a key metabolism enzyme which regulates the network of FFAs in numerous aggressive tumors, such as colorectal cancer, neuroblastoma and nasopharyngeal carcinoma, by enabling tumor cells to mobilize. Considering the abundance and importance of FFAs and lipid metabolism in the liver, we predict that MAGL will be essential to the initiation and progression of HCC, perhaps more so than the other aforementioned cancers. The role and mechanism of MAGL in HCC carcinogenesis and progression remain unclear.
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