Abstract
BackgroundMonoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown.MethodsIn this study, we used a tissue microarray containing samples from 170 HCC patients to evaluate the expression of MAGL and its correlation with other clinicopathologic characteristics. In addition, we investigated the regulating effects of MAGL on various HCC lines. Finally, we identified the NF-κB signaling pathway participated in MAGL-mediated epithelial-mesenchymal transition (EMT) using HCC cell lines with different metastatic potentials.ResultsThe expression of MAGL was significantly higher in HCC tumors than in matched peritumor tissues. Specifically, high MAGL expression was found in tumors with larger tumor size, microvascular invasion, poor differentiation, or advanced TNM stage. In addition, the clinical prognosis for the MAGLhigh group was markedly poorer than that for the MAGLlow group in the 1-, 3-, and 5-year overall survival times and recurrence rates of HCC patients. MAGL expression was an independent prognostic factor for both survival and recurrence after curative resection. Furthermore, the upregulation of MAGL in HCC cells promoted cell growth and invasiveness abilities, and accompanied by EMT. In contrast, downregulation of MAGL obviously inhibited these characteristics. Moreover, further investigations verified that MAGL facilitates HCC progression via NF-κB-mediated EMT process.ConclusionsOur findings demonstrate MAGL could promote HCC progression by the induction of EMT and suggest a potential therapeutic target, as well as a biomarker for prognosis, in patients with HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0361-3) contains supplementary material, which is available to authorized users.
Highlights
Monoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown
Expression of MAGL is upregulated in HCC patients and associated with recurrence To investigate the effects of MAGL in HCC, we first detected MAGL expression in 27 tumor samples by immunohistochemical assay and found that MAGL expression was obviously elevated in HCC tissues compared with paired peritumor tissues (Fig. 1a)
Western blot and quantitative real-time PCR (qRT-PCR) analysis of the indicated HCC patients demonstrated that the average expression of MAGL on both protein and mRNA levels were significantly higher in HCC tissues than peritumor tissues (Fig. 1b, c)
Summary
Monoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown. MAGL plays a key role in several physiological processes including pain and nociperception through hydrolysis of the endocannabinoid 2-arachidonoylglycerol [14, 15]. Emerging studies have identified that expression of MAGL is elevated in many types of cancers, including melanoma, ovarian, and breast cancer [16]. MAGL could facilitate cancer cell proliferation and aggressiveness through the production of signaling lipids including monoacylglycerol (MAGs), FFA, and secondary lipid metabolites (especially LPA/PGE2). EMT-related markers are predictors for increased invasion, metastasis, and poor prognosis in some human tumor types [19]. Little is known about the physiological role of MAGL in human HCC progression
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